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  • 1.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    The Affinity Binder Knockdown Initiative.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 2.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO).
    Lundberg, Emma
    KTH, School of Biotechnology (BIO).
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO).
    The Affinity Binder Knockdown Initiative2015In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 26Article in journal (Other academic)
  • 3.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO).
    von Feilitzen, Kalle
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO).
    Antibodypedia - The wiki of antibodies2015In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 26Article in journal (Other academic)
  • 4.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    von Feilitzen, Kalle
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    ANTIBODYPEDIA: THE WIKI OF ANTIBODIES2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 5. Arstikaitis, Pamela
    et al.
    Gauthier-Campbell, Catherine
    Gutierrez Herrera, Rosario Carolina
    Huang, Kun
    Levinson, Joshua N.
    Murphy, Timothy H.
    Kilimann, Manfred W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Sala, Carlo
    Colicos, Michael A.
    El-Husseini, Alaa
    Paralemmin-1, a modulator of filopodia induction is required for spine maturation2008In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 19, no 5, p. 2026-2038Article in journal (Refereed)
    Abstract [en]

    Dendritic filopodia are thought to participate in neuronal contact formation and development of dendritic spines, however, molecules that regulate filopodia extension and their maturation to spines remain largely unknown. Here we identify paralemmin-1 as a regulator of filopodia induction and spine maturation. Paralemmin-1 localizes to dendritic membranes, and its ability to induce filopodia and recruit synaptic elements to contact sites requires protein acylation. Effects of paralemmin-1 on synapse maturation are modulated by alternative splicing that regulates spine formation and recruitment of AMPA-type glutamate receptors. Paralemmin-1 enrichment at the plasma membrane is subject to rapid changes in neuronal excitability, and this process controls neuronal activity-driven effects on protrusion expansion. Knockdown of paralemmin-1 in developing neurons reduces the number of filopodia and spines formed and diminishes the effects of Shank1b on the transformation of existing filopodia into spines. Our study identifies a key role for paralemmin-1 in spine maturation through modulation of filopodia induction.

  • 6. Bareth, Bettina
    et al.
    Nikolov, Miroslav
    Lorenzi, Isotta
    Hildenbeutel, Markus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mick, David U.
    Helbig, Christin
    Urlaub, Henning
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rehling, Peter
    Dennerlein, Sven
    Oms1 associates with cytochrome c oxidase assembly intermediates to stabilize newly synthesized Cox12016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27, no 10, p. 1570-1580Article in journal (Refereed)
    Abstract [en]

    The mitochondrial cytochrome c oxidase assembles in the inner membrane from subunits of dual genetic origin. The assembly process of the enzyme is initiated by membrane insertion of the mitochondria-encoded Cox1 subunit. During complex maturation, transient assembly intermediates, consisting of structural subunits and specialized chaperone-like assembly factors, are formed. In addition, cofactors such as heme and copper have to be inserted into the nascent complex. To regulate the assembly process, the availability of Cox1 is under control of a regulatory feedback cycle in which translation of COX1 mRNA is stalled when assembly intermediates of Cox1 accumulate through inactivation of the translational activator Mss51. Here we isolate a cytochrome c oxidase assembly intermediate in preparatory scale from coa1 Delta. mutant cells, using Mss51 as bait. We demonstrate that at this stage of assembly, the complex has not yet incorporated the heme a cofactors. Using quantitative mass spectrometry, we define the protein composition of the assembly intermediate and unexpectedly identify the putative methyltransferase Oms1 as a constituent. Our analyses show that Oms1 participates in cytochrome c oxidase assembly by stabilizing newly synthesized Cox1.

  • 7. Bauerschmitt, Heike
    et al.
    Mick, David
    Deckers, Markus
    Vollmer, C
    Funes, S
    Kehrein, Kirsten
    University of Kaiserslautern, Germany.
    Ott, Martin
    University of Kaiserslautern, Germany.
    Rehling, Peter
    Herrmann, Johannes
    Ribosome-binding proteins Mdm38 and Mba1 display overlapping functions for regulation of mitochondrial translation2010In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 21, no 12, p. 1937-1944Article in journal (Other academic)
    Abstract [en]

    Biogenesis of respiratory chain complexes depends on the expression of mitochondrial-encoded subunits. Their synthesis occurs on membrane-associated ribosomes and is probably coupled to their membrane insertion. Defects in expression of mitochondrial translation products are among the major causes of mitochondrial disorders. Mdm38 is related to Letm1, a protein affected in Wolf-Hirschhorn syndrome patients. Like Mba1 and Oxa1, Mdm38 is an inner membrane protein that interacts with ribosomes and is involved in respiratory chain biogenesis. We find that simultaneous loss of Mba1 and Mdm38 causes severe synthetic defects in the biogenesis of cytochrome reductase and cytochrome oxidase. These defects are not due to a compromised membrane binding of ribosomes but the consequence of a mis-regulation in the synthesis of Cox1 and cytochrome b. Cox1 expression is restored by replacing Cox1-specific regulatory regions in the mRNA. We conclude, that Mdm38 and Mba1 exhibit overlapping regulatory functions in translation of selected mitochondrial mRNAs.

  • 8. Bjork, L.
    et al.
    Ait Blal, C.
    Alm, Tove L.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bäckström, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Gnann, C.
    Hjelmare, Martin
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schutten, Rutger
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Skogs, Marie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Stadler, Charlotte
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Application specific antibody validation. The Human Protein Atlas validation scheme and how to confirm subcellular protein localization.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 9.
    Björk, Petra
    et al.
    Stockholm University.
    Baurén, Göran
    Stockholm University.
    Jin, ShaoBo
    Stockholm University.
    Tong, Yong-Guang
    Karolinska Institutet.
    Bürglin, Thomas R.
    Karolinska Institutet.
    Hellman, Ulf
    Ludwig Institute for Cancer Research.
    Wieslander, Lars
    Stockholm University.
    A novel conserved RNA-binding domain protein, RBD-1, is essential for ribosome biogenesis2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, no 10, p. 3683-3695Article in journal (Refereed)
    Abstract [en]

    Synthesis of the ribosomal subunits from pre-rRNA requires a large number of trans-acting proteins and small nucleolar ribonucleoprotein particles to execute base modifications, RNA cleavages, and structural rearrangements. We have characterized a novel protein, RNA-binding domain-1 (RBD-1), that is involved in ribosome biogenesis. This protein contains six consensus RNA-binding domains and is conserved as to sequence, domain organization, and cellular location from yeast to human. RBD-1 is essential in Caenorhabditis elegans. In the dipteran Chironomus tentans, RBD-1 (Ct-RBD-1) binds pre-rRNA in vitro and anti-Ct-RBD-1 antibodies repress pre-rRNA processing in vivo. Ct-RBD-1 is mainly located in the nucleolus in an RNA polymerase I transcription-dependent manner, but it is also present in discrete foci in the interchromatin and in the cytoplasm. In cytoplasmic extracts, 20-30% of Ct-RBD-1 is associated with ribosomes and, preferentially, with the 40S ribosomal subunit. Our data suggest that RBD-1 plays a role in structurally coordinating pre-rRNA during ribosome biogenesis and that this function is conserved in all eukaryotes.

  • 10. Björk, Petra
    et al.
    Baurén, Göran
    Jin, ShaoBo
    Tong, Yong-Guang
    Bürglin, Thomas R.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Wieslander, Lars
    A novel conserved RNA-binding domain protein, RBD-1, is essential for ribosome biogenesis2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, no 10, p. 3683-3695Article in journal (Refereed)
    Abstract [en]

    Synthesis of the ribosomal subunits from pre-rRNA requires a large number of trans-acting proteins and small nucleolar ribonucleoprotein particles to execute base modifications, RNA cleavages, and structural rearrangements. We have characterized a novel protein, RNA-binding domain-1 (RBD-1), that is involved in ribosome biogenesis. This protein contains six consensus RNA-binding domains and is conserved as to sequence, domain organization, and cellular location from yeast to human. RBD-1 is essential in Caenorhabditis elegans. In the dipteran Chironomus tentans, RBD-1 (Ct-RBD-1) binds pre-rRNA in vitro and anti-Ct-RBD-1 antibodies repress pre-rRNA processing in vivo. Ct-RBD-1 is mainly located in the nucleolus in an RNA polymerase I transcription-dependent manner, but it is also present in discrete foci in the interchromatin and in the cytoplasm. In cytoplasmic extracts, 20-30% of Ct-RBD-1 is associated with ribosomes and, preferentially, with the 40S ribosomal subunit. Our data suggest that RBD-1 plays a role in structurally coordinating pre-rRNA during ribosome biogenesis and that this function is conserved in all eukaryotes.

  • 11.
    Björk, Petra
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Baurén, Göran
    Jin, ShaoBo
    Tong, Yong-Guang
    Bürglin, Thomas R.
    Hellman, Ulf
    Wieslander, Lars
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A Novel Conserved RNA-binding Domain Protein, RBD-1, Is Essential For Ribosome Biogenesis2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, p. 3683-3695Article in journal (Refereed)
    Abstract [en]

    Synthesis of the ribosomal subunits from pre-rRNA requires a large number of trans-acting proteins and small nucleolar ribonucleoprotein particles to execute base modifications, RNA cleavages, and structural rearrangements. We have characterized a novel protein, RNA-binding domain-1 (RBD-1), that is involved in ribosome biogenesis. This protein contains six consensus RNA-binding domains and is conserved as to sequence, domain organization, and cellular location from yeast to human. RBD-1 is essential in Caenorhabditis elegans. In the dipteran Chironomus tentans, RBD-1 (Ct-RBD-1) binds pre-rRNA in vitro and anti-Ct-RBD-1 antibodies repress pre-rRNA processing in vivo. Ct-RBD-1 is mainly located in the nucleolus in an RNA polymerase I transcription-dependent manner, but it is also present in discrete foci in the interchromatin and in the cytoplasm. In cytoplasmic extracts, 20-30% of Ct-RBD-1 is associated with ribosomes and, preferentially, with the 40S ribosomal subunit. Our data suggest that RBD-1 plays a role in structurally coordinating pre-rRNA during ribosome biogenesis and that this function is conserved in all eukaryotes.

  • 12.
    Blomgran, Robert
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Stendalh, O
    Linkoping Univ, IHM, SE-58185 Linkoping, Sweden.
    Zheng, Limin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Activation of Protein Kinase B in human monocytic U937 cells by Salmonella typhimurium2001In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 12, p. 1794-Conference paper (Other academic)
  • 13.
    Buschke, Susanne
    et al.
    Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
    Stark, Hans-Jürgen
    Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
    Cerezo, Ana
    Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
    Prätzel-Wunder, Silke
    Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
    Boehnke, Karsten
    Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
    Kollar, Jasmin
    Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
    Langbein, Lutz
    Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Boukamp, Petra
    Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
    A decisive function of transforming growth factor-β/Smad signaling in tissue morphogenesis and differentiation of human HaCaT keratinocytes2011In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 22, no 6, p. 782-794Article in journal (Refereed)
    Abstract [en]

    The mechanism by which transforming growth factor-β (TGFβ) regulates differentiation in human epidermal keratinocytes is still poorly understood. To assess the role of Smad signaling, we engineered human HaCaT keratinocytes either expressing small interfering RNA against Smads2, 3, and 4 or overexpressing Smad7 and verified impaired Smad signaling as decreased Smad phosphorylation, aberrant nuclear translocation, and altered target gene expression. Besides abrogation of TGFβ-dependent growth inhibition in conventional cultures, epidermal morphogenesis and differentiation in organotypic cultures were disturbed, resulting in altered tissue homeostasis with suprabasal proliferation and hyperplasia upon TGFβ treatment. Neutralizing antibodies against TGFβ, similar to blocking the actions of EGF-receptor or keratinocyte growth factor, caused significant growth reduction of Smad7-overexpressing cells, thereby demonstrating that epithelial hyperplasia was attributed to TGFβ-induced "dermis"-derived growth promoting factors. Furthermore impaired Smad signaling not only blocked the epidermal differentiation process or caused epidermal-to-mesenchymal transition but induced a switch to a complex alternative differentiation program, best characterized as mucous/intestinal-type epithelial differentiation. As the same alternative phenotype evolved from both modes of Smad-pathway interference, and reduction of Smad7-overexpression caused reversion to epidermal differentiation, our data suggest that functional TGFβ/Smad signaling, besides regulating epidermal tissue homeostasis, is not only essential for terminal epidermal differentiation but crucial in programming different epithelial differentiation routes.

  • 14. Caceres, R.
    et al.
    Bojanala, N.
    Kelley, L. C.
    Dreier, Jes
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Manzi, J.
    Di Federico, F.
    Chi, Q.
    Risler, T.
    Testa, Ilaria
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Sherwood, D. R.
    Plastino, J.
    WASP and WAVE activate the Arp2/3 complex for actin-based force production during basement membrane invasion.2017In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 28Article in journal (Other academic)
  • 15.
    Capaldo, Christopher T.
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Kwon, Michael
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Laur, Oskar
    Yerkes-Microbiology, Emory University, Atlanta, GA, USA.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation2011In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 22, no 10, p. 1677-1685Article in journal (Refereed)
    Abstract [en]

    Coordinated regulation of cell proliferation is vital for epithelial tissue homeostasis, and uncontrolled proliferation is a hallmark of carcinogenesis. A growing body of evidence indicates that epithelial tight junctions (TJs) play a role in these processes, although the mechanisms involved are poorly understood. In this study, we identify and characterize a novel plasma membrane pool of cyclin D1 with cell-cycle regulatory functions. We have determined that the zonula occludens (ZO) family of TJ plaque proteins sequesters cyclin D1 at TJs during mitosis, through an evolutionarily conserved class II PSD-95, Dlg, and ZO-1 (PDZ)-binding motif within cyclin D1. Disruption of the cyclin D1/ZO complex through mutagenesis or siRNA-mediated suppression of ZO-3 resulted in increased cyclin D1 proteolysis and G(0)/G(1) cell-cycle retention. This study highlights an important new role for ZO family TJ proteins in regulating epithelial cell proliferation through stabilization of cyclin D1 during mitosis.

  • 16. Carmichael, J B
    et al.
    Provost, P
    Ekwall, Karl
    Södertörn University, School of Chemistry, Biology, Geography and Environmental Science.
    Hobman, T C
    Ago1 and Dcr1, two core components of the RNA interference pathway, functionally diverge from Rdp1 in regulating cell cycle events in Schizosaccharomyces pombe2004In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 15, no 3, p. 1425-1435Article in journal (Refereed)
    Abstract [en]

    In the fission yeast Schizosaccharomyces pombe, three genes that function in the RNA interference (RNAi) pathway, ago1(+), dcr1(+), and rdp1(+), have recently been shown to be important for timely formation of heterochromatin and accurate chromosome segregation. In the present study, we present evidence that null mutants for ago1(+) and dcr1(+) but not rdp1(+), exhibit abnormal cytokinesis, cell cycle arrest deficiencies, and mating defects. Subsequent analyses showed that ago1(+) and dcr1(+) are required for regulated hyperphosphorylation of Cdc2 when encountering genotoxic insults. Because rdp1(+) is dispensable for this process, the functions of ago1(+) and dcr1(+) in this pathway are presumably independent of their roles in RNAi-mediated heterochromatin formation and chromosome segregation. This was further supported by the finding that ago1(+) is a multicopy suppressor of the S-M checkpoint deficiency and cytokinesis defects associated with loss of Dcr1 function, but not for the chromosome segregation defects of this mutant. Accordingly, we conclude that Dcr1-dependent production of small interfering RNAs is not required for enactment and/or maintenance of certain cell cycle checkpoints and that Ago1 and Dcr1 functionally diverge from Rdp1 to control cell cycle events in fission yeast. Finally, exogenous expression of hGERp95/EIF2C2/hAgo2, a human Ago1 homolog implicated in posttranscriptional gene silencing, compensated for the loss of ago1(+) function in S. pombe. This suggests that PPD proteins may also be important for regulation of cell cycle events in higher eukaryotes.

  • 17.
    Cho, S. Ei
    et al.
    Stanford Univ, Biol, Stanford, CA USA.
    Roy, J.
    Stanford Univ, Biol, Stanford, CA USA.
    Ivarsson, Ylva
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Cyert, M. S.
    Stanford Univ, Biol, Stanford, CA USA.
    Investigating the phospho-regulation of ER shaping protein RTN1A (Reticulon-1A) by the Calcineurin phosphatase.2017In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 28, no 26, p. 3727-3727Article in journal (Other academic)
  • 18. Chotard, Laëtitia
    et al.
    Mishra, Ashwini K
    Sylvain, Marc-André
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lambright, David G
    Rocheleau, Christian E
    TBC-2 regulates RAB-5/RAB-7-mediated endosomal trafficking in Caenorhabditis elegans2010In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 21, no 13, p. 2285-2296Article in journal (Refereed)
    Abstract [en]

    During endosome maturation the early endosomal Rab5 GTPase is replaced with the late endosomal Rab7 GTPase. It has been proposed that active Rab5 can recruit and activate Rab7, which in turn could inactivate and remove Rab5. However, many of the Rab5 and Rab7 regulators that mediate endosome maturation are not known. Here, we identify Caenorhabditis elegans TBC-2, a conserved putative Rab GTPase-activating protein (GAP), as a regulator of endosome to lysosome trafficking in several tissues. We show that tbc-2 mutant animals accumulate enormous RAB-7-positive late endosomes in the intestine containing refractile material. RAB-5, RAB-7, and components of the homotypic fusion and vacuole protein sorting (HOPS) complex, a RAB-7 effector/putative guanine nucleotide exchange factor (GEF), are required for the tbc-2(-) intestinal phenotype. Expression of activated RAB-5 Q78L in the intestine phenocopies the tbc-2(-) large late endosome phenotype in a RAB-7 and HOPS complex-dependent manner. TBC-2 requires the catalytic arginine-finger for function in vivo and displays the strongest GAP activity on RAB-5 in vitro. However, TBC-2 colocalizes primarily with RAB-7 on late endosomes and requires RAB-7 for membrane localization. Our data suggest that TBC-2 functions on late endosomes to inactivate RAB-5 during endosome maturation.

  • 19. Chou, Wan-Chih
    et al.
    Prokova, Vassiliki
    Shiraishi, Keiko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Valcourt, Ulrich
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Hadzopoulou-Cladaras, Margarita
    Zannis, Vassilis I.
    Kardassis, Dimitris
    Mechanism of a transcriptional cross talk between transforming growth factor-beta-regulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-42003In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 3, p. 1279-1294Article in journal (Refereed)
    Abstract [en]

    We have shown previously that the transforming growth factor-beta (TGFbeta)-regulated Sma-Mad (Smad) protein 3 and Smad4 proteins transactivate the apolipoprotein C-III promoter in hepatic cells via a hormone response element that binds the nuclear receptor hepatocyte nuclear factor 4 (HNF-4). In the present study, we show that Smad3 and Smad4 but not Smad2 physically interact with HNF-4 via their Mad homology 1 domains both in vitro and in vivo. The synergistic transactivation of target promoters by Smads and HNF-4 was shown to depend on the specific promoter context and did not require an intact beta-hairpin/DNA binding domain of the Smads. Using glutathione S-transferase interaction assays, we established that two regions of HNF-4, the N-terminal activation function 1 (AF-1) domain (aa 1-24) and the C-terminal F domain (aa 388-455) can mediate physical Smad3/HNF-4 interactions in vitro. In vivo, Smad3 and Smad4 proteins enhanced the transactivation function of various GAL4-HNF-4 fusion proteins via the AF-1 and the adjacent DNA binding domain, whereas a single tyrosine to alanine substitution in AF-1 abolished coactivation by Smads. The findings suggest that the transcriptional cross talk between the TGFbeta-regulated Smads and HNF-4 is mediated by specific functional domains in the two types of transcription factors. Furthermore, the specificity of this interaction for certain target promoters may play an important role in various hepatocyte functions, which are regulated by TGFbeta and the Smads.

  • 20. Cortese, Katia
    et al.
    Howes, Mark T.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Tagliatti, Erica
    Bagnato, Paola
    Petrelli, Annalisa
    Bono, Maria
    McMahon, Harvey T.
    Parton, Robert G.
    Tacchetti, Carlo
    The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments2013In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 24, no 2, p. 129-144Article in journal (Refereed)
    Abstract [en]

    The ErbB2 receptor is a clinically validated cancer target whose internalization and trafficking mechanisms remain poorly understood. HSP90 inhibitors, such as geldanamycin (GA), have been developed to target the receptor to degradation or to modulate downstream signaling. Despite intense investigations, the entry route and postendocytic sorting of ErbB2 upon GA stimulation have remained controversial. We report that ErbB2 levels inversely impact cell clathrin-mediated endocytosis (CME) capacity. Indeed, the high levels of the receptor are responsible for its own low internalization rate. GA treatment does not directly modulate ErbB2 CME rate but it affects ErbB2 recycling fate, routing the receptor to modified multivesicular endosomes (MVBs) and lysosomal compartments, by perturbing early/recycling endosome structure and sorting capacity. This activity occurs irrespective of the cargo interaction with HSP90, as both ErbB2 and the constitutively recycled, HSP90-independent, transferrin receptor are found within modified endosomes, and within aberrant, elongated recycling tubules, leading to modified MVBs/lysosomes. We propose that GA, as part of its anticancer activity, perturbs early/recycling endosome sorting, routing recycling cargoes toward mixed endosomal compartments.

  • 21.
    Cross, Michael J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lu, Lingge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nyqvist, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Holmqvist, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulatesthe Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, no 8, p. 2881-2893Article in journal (Refereed)
    Abstract [en]

    Stimulation of fibroblast growth factor receptor-1 (FGFR-1) is known to result in phosphorylation of tyrosine 766 and the recruitment and subsequent activation of phospholipase C-γ (PLC-γ). To assess the role of tyrosine 766 in endothelial cell function, we generated endothelial cells expressing a chimeric receptor, composed of the extracellular domain of the PDGF receptor-α and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC-γ activation and resulted in a reduced phosphorylation of FRS2 and reduced activation of the Ras/MEK/MAPK pathway relative to the wild-type chimeric receptor. However, FGFR-1–mediated MAPK activation was not dependent on PKC activation or intracellular calcium, both downstream mediators of PLC-γ activation. We report that the adaptor protein Shb is also able to bind tyrosine 766 in the FGFR-1, via its SH2 domain, resulting in its subsequent phosphorylation. Overexpression of an SH2 domain mutant Shb caused a dramatic reduction in FGFR-1–mediated FRS2 phosphorylation with concomitant perturbment of the Ras/MEK/MAPK pathway. Expression of the chimeric receptor mutant and the Shb SH2 domain mutant resulted in a similar reduction in FGFR-1–mediated mitogenicity. We conclude, that Shb binds to tyrosine 766 in the FGFR-1 and regulates FGF-mediated mitogenicity via FRS2 phosphorylation and the subsequent activation of the Ras/MEK/MAPK pathway.

  • 22.
    Danielsson, Frida
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Akesson, L.
    Skogs, Marie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Profiling changes in response to hypoxia in a four-step cell line model for malignant transformation.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 23.
    Danielsson, Frida
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlen, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gad, A. K.
    Profiling the Molecular changes during malignant transformation and response to different oxygen levels, using a combined transcriptomics and proteomics approach2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, article id P1845Article in journal (Other academic)
  • 24.
    Danielsson, Frida
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Skogs, Marie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Åkesson, L.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Mahdessian, Diana
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Sullivan, Devin P.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Thul, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Wiking, Mikaela
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Björk, L.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Schutten, Rutger
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Ait Blal, Carl
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Hjelmare, Martin
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Gnann, Christian
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    An image-based view of the microtubule proteome2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 25. Doherty, Gary J.
    et al.
    Åhlund, Monika K.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Howes, Mark T.
    Moren, Bjorn
    Parton, Robert G.
    McMahon, Harvey T.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The endocytic protein GRAF1 is directed to cell-matrix adhesion sites and regulates cell spreading2011In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 22, no 22, p. 4380-4389Article in journal (Refereed)
    Abstract [en]

    The rho GTPase-activating protein GTPase regulator associated with focal adhesion kinase-1 (GRAF1) remodels membranes into tubulovesicular clathrin-independent carriers (CLICs) mediating lipid-anchored receptor endocytosis. However, the cell biological functions of this highly prevalent endocytic pathway are unclear. In this article, we present biochemical and cell biological evidence that GRAF1 interacted with a network of endocytic and adhesion proteins and was found enriched at podosome-like adhesions and src-induced podosomes. We further demonstrate that these sites comprise microdomains of highly ordered lipid enriched in GRAF1 endocytic cargo. GRAF1 activity was upregulated in spreading cells and uptake via CLICs was concentrated at the leading edge of migrating cells. Depletion of GRAF1, which inhibits CLIC generation, resulted in profound defects in cell spreading and migration. We propose that GRAF1 remodels membrane microdomains at adhesion sites into endocytic carriers, facilitating membrane turnover during cell morphological changes.

  • 26.
    Dou, Dan
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    da Silva, Diogo V.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nordholm, Johan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wang, Hao
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Daniels, Robert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Type II transmembrane domain hydrophobicity dictates the cotranslational dependence for inversion2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, no 21, p. 3363-3374Article in journal (Refereed)
    Abstract [en]

    Membrane insertion by the Sec61 translocon in the endoplasmic reticulum (ER) is highly dependent on hydrophobicity. This places stringent hydrophobicity requirements on transmembrane domains (TMDs) from single-spanning membrane proteins. On examining the single-spanning influenza A membrane proteins, we found that the strict hydrophobicity requirement applies to the N-out-C-in HA and M2 TMDs but not the N-in-C-out TMDs from the type II membrane protein neuraminidase (NA). To investigate this discrepancy, we analyzed NA TMDs of varying hydrophobicity, followed by increasing polypeptide lengths, in mammalian cells and ER microsomes. Our results show that the marginally hydrophobic NA TMDs (Delta G(app) > 0 kcal/mol) require the cotranslational insertion process for facilitating their inversion during translocation and a positively charged N-terminal flanking residue and that NA inversion enhances its plasma membrane localization. Overall the cotranslational inversion of marginally hydrophobic NA TMDs initiates once similar to 70 amino acids past the TMD are synthesized, and the efficiency reaches 50% by similar to 100 amino acids, consistent with the positioning of this TMD class in type II human membrane proteins. Inversion of the M2 TMD, achieved by elongating its C-terminus, underscores the contribution of cotranslational synthesis to TMD inversion.

  • 27.
    Edlund, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Bu, Shizhong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Schuster, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heuchel, Rainer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Landström, Maréne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Transforming growth factor-beta1-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 32003In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 2, p. 529-544Article in journal (Refereed)
    Abstract [en]

    The inhibitory Smad7, a direct target gene for transforming growth factor-beta (TGF-beta), mediates TGF-beta1-induced apoptosis in several cell types. Herein, we report that apoptosis of human prostate cancer PC-3U cells induced by TGF-beta1 or Smad7 overexpression is caused by a specific activation of the p38 mitogen-activated protein kinase pathway in a TGF-beta-activated kinase 1 (TAK1)- and mitogen-activated protein kinase kinase 3 (MKK3)-dependent manner. Expression of dominant negative p38, dominant negative MKK3, or incubation with the p38 selective inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], prevented TGF-beta1-induced apoptosis. The expression of Smad7 was required for TGF-beta-induced activation of MKK3 and p38 kinases, and endogenous Smad7 was found to interact with phosphorylated p38 in a ligand-dependent manner. Ectopic expression of wild-type TAK1 promoted TGF-beta1-induced phosphorylation of p38 and apoptosis, whereas dominant negative TAK1 reduced TGF-beta1-induced phosphorylation of p38 and apoptosis. Endogenous Smad7 was found to interact with TAK1, and TAK1, MKK3, and p38 were coimmunoprecipitated with Smad7 in transiently transfected COS1 cells. Moreover, ectopically expressed Smad7 enhanced the coimmunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38.

  • 28.
    Edlund, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Landström, Maréne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Transforming growth factor-beta-induced mobilization of actin cytoskeleton required signaling by small GTPases Cdc42 and RhoA2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, no 3, p. 902-914Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF-beta) is a potent regulator of cell growth and differentiation in many cell types. The Smad signaling pathway constitutes a main signal transduction route downstream of TGF-beta receptors. We studied TGF-beta-induced rearrangements of the actin filament system and found that TGF-beta 1 treatment of PC-3U human prostate carcinoma cells resulted in a rapid formation of lamellipodia. Interestingly, this response was shown to be independent of the Smad signaling pathway; instead, it required the activity of the Rho GTPases Cdc42 and RhoA, because ectopic expression of dominant negative mutant Cdc42 and RhoA abrogated the response. Long-term stimulation with TGF-beta 1 resulted in an assembly of stress fibers; this response required both signaling via Cdc42 and RhoA, and Smad proteins. A known downstream effector of Cdc42 is p38(MAPK); treatment of the cells with the p38(MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), as well as ectopic expression of a kinase-inactive p38(MAPK), abrogated the TGF-beta-induced actin reorganization. Moreover, treatment of cells with the inhibitors of the RhoA target-protein Rho-associated coiled-coil kinase (+)-R-trans-4-(aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide (Y-27632) and 1-5(-isoquinolinesulfonyl)homopiperazine (HA-1077), as well as ectopic expression of kinase-inactive Rho coiled-coil kinase-1, abrogated the TGF-beta 1-induced formation of stress fibers. Collectively, these data indicate that TGF-beta-induced membrane ruffles occur via Rho GTPase-dependent pathways, whereas long-term effects require cooperation between Smad and Rho GTPase signaling pathways.

  • 29.
    Efimenko, Evgeni
    et al.
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Blacque, Oliver E.
    Simon Fraser University, Burnaby, British Columbia, Canada.
    Ou, Guangshuo
    University of California, Davis, USA.
    Haycraft, Courtney J.
    University of Alabama at Birmingham Medical Center, Birmingham, USA.
    Yoder, Bradley K.
    University of Alabama at Birmingham Medical Center, Birmingham, USA.
    Scholey, Jonathan M.
    University of California, Davis, USA.
    Leroux, Michel R.
    Simon Fraser University, Burnaby, British Columbia, Canada.
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Instiute.
    Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory Cilia2006In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 17, no 11, p. 4801-4811Article in journal (Refereed)
    Abstract [en]

    The intraflagellar transport (IFT) machinery required to build functional cilia consists of a multisubunit complex whose molecular composition, organization, and function are poorly understood. Here, we describe a novel tryptophan-aspartic acid (WD) repeat (WDR) containing IFT protein from Caenorhabditis elegans, DYF-2, that plays a critical role in maintaining the structural and functional integrity of the IFT machinery. We determined the identity of the dyf-2 gene by transgenic rescue of mutant phenotypes and by sequencing of mutant alleles. Loss of DYF-2 function selectively affects the assembly and motility of different IFT components and leads to defects in cilia structure and chemosensation in the nematode. Based on these observations, and the analysis of DYF-2 movement in a Bardet-Biedl syndrome mutant with partially disrupted IFT particles, we conclude that DYF-2 can associate with IFT particle complex B. At the same time, mutations in dyf-2 can interfere with the function of complex A components, suggesting an important role of this protein in the assembly of the IFT particle as a whole. Importantly, the mouse orthologue of DYF-2, WDR19, also localizes to cilia, pointing to an important evolutionarily conserved role for this WDR protein in cilia development and function.

  • 30. Ekman, Maria
    et al.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lee, So Young
    Edlund, Sofia
    Kozakai, Takaharu
    Thakur, Noopur
    Tran, Hoanh
    Qian, Jiang
    Groeden, Joanna
    Heldin, Carl-Henrik
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    APC and Smad7 link TGF beta type I receptors to the microtubule system to promote cell migration2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 11, p. 2109-2121Article in journal (Refereed)
    Abstract [en]

    Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3 beta (GSK-3 beta). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-beta (TGF beta) and is known to inhibit various TGF beta-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGF beta stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3 beta kinases to facilitate local TGF beta/p38-dependent inactivation of GSK-3 beta, accumulation of beta-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGF beta type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF beta.

  • 31.
    Ekman, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Mu, Yabing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lee, So Young
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Edlund, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Kozakai, Takaharu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Thakur, Noopur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Tran, Hoanh
    Qian, Jiang
    Groeden, Joanna
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Landström, Maréne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    APC and Smad7 link the TGFβ type I receptors to the microtubule system to promote cell migration2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 11, p. 2109-2121Article in journal (Refereed)
    Abstract [en]

    Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3 beta (GSK-3 beta). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-beta (TGF beta) and is known to inhibit various TGF beta-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGF beta stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3 beta kinases to facilitate local TGF beta/p38-dependent inactivation of GSK-3 beta, accumulation of beta-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGF beta type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF beta.

  • 32. Elliott, Kerryn L.
    et al.
    Svanström, Andreas
    Spiess, Matthias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Karlsson, Roger
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Grantham, Julie
    A novel function of the monomeric CCT epsilon subunit connects the serum response factor pathway to chaperone-mediated actin folding2015In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 26, no 15, p. 2801-2809Article in journal (Refereed)
    Abstract [en]

    Correct protein folding is fundamental for maintaining protein homeostasis and avoiding the formation of potentially cytotoxic protein aggregates. Although some proteins appear to fold unaided, actin requires assistance from the oligomeric molecular chaperone CCT. Here we report an additional connection between CCT and actin by identifying one of the CCT subunits, CCT epsilon, as a component of the myocardin-related cotranscription factor-A (MRTF-A)/serum response factor (SRF) pathway. The SRF pathway registers changes in G-actin levels, leading to the transcriptional up-regulation of a large number of genes after actin polymerization. These genes encode numerous actin-binding proteins as well as actin. We show that depletion of the CCT epsilon subunit by siRNA enhances SRF signaling in cultured mammalian cells by an actin assembly-independent mechanism. Overexpression of CCTe in its monomeric form revealed that CCT epsilon binds via its substrate-binding domain to the C-terminal region of MRTF-A and that CCT epsilon is able to alter the nuclear accumulation of MRTF-A after stimulation by serum addition. Given that the levels of monomeric CCT epsilon conversely reflect the levels of CCT oligomer, our results suggest that CCT epsilon provides a connection between the actin-folding capacity of the cell and actin expression.

  • 33.
    Ferletta, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kikkawa, Yamato
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Yu, Hao
    Talts, Jan F
    Durbeej, Madeleine
    Sonnenberg, Arnoud
    Timpl, Rupert
    Campbell, Kevin P
    Ekblom, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Genersch, Elke
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Opposing roles of integrin alpha6Abeta1 and dystroglycan in laminin-mediated extracellular signal-regulated kinase activation2003In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 5, p. 2088-2103Article in journal (Refereed)
    Abstract [en]

    Laminin-integrin interactions can in some settings activate the extracellular signal-regulated kinases (ERKs) but the control mechanisms are poorly understood. Herein, we studied ERK activation in response to two laminins isoforms (-1 and -10/11) in two epithelial cell lines. Both cell lines expressed beta1-containing integrins and dystroglycan but lacked integrin alpha6beta4. Antibody perturbation assays showed that both cell lines bound to laminin-10/11 via the alpha3beta1and alpha6beta1 integrins. Although laminin-10/11 was a stronger adhesion complex than laminin-1 for both cell lines, both laminins activated ERK in only one of the two cell lines. The ERK activation was mediated by integrin alpha6beta1 and not by alpha3beta1 or dystroglycan. Instead, we found that dystroglycan-binding domains of both laminin-1 and -10/11 suppressed integrin alpha6beta1-mediated ERK activation. Moreover, the responding cell line expressed the two integrin alpha6 splice variants, alpha6A and alpha6B, whereas the nonresponding cell line expressed only alpha6B. Furthermore, ERK activation was seen in cells transfected with the integrin alpha6A subunit, but not in alpha6B-transfected cells. We conclude that laminin-1 and -10/11 share the ability to induce ERK activation, that this is regulated by integrin alpha6Abeta1, and suggest a novel role for dystroglycan-binding laminin domains as suppressors of this activation.

  • 34.
    Fontana, Jacopo M.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Bernhem, Kristoffer
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Zhang, L.
    Karolinska Inst, Dept Pediat Cell Mol Biol, Stockholm, Sweden..
    Nilsson, Linnea
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Aperia, A.
    Karolinska Inst, Dept Pediat Cell Mol Biol, Stockholm, Sweden..
    Ouabain, a Na, K-ATPase ligand, intervenes with the onset of glucose-triggered apoptosis2015In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 26Article in journal (Other academic)
  • 35.
    Gad, Annica K. B.
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Nehru, Vishal
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Ruusala, Aino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Aspenström, Pontus
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    RhoD regulates cytoskeletal dynamics via the actin nucleation-promoting factor WASp homologue associated with actin Golgi membranes and microtubules2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 24, p. 4807-4819Article in journal (Refereed)
    Abstract [en]

    The Rho GTPases have mainly been studied in association with their roles in the regulation of actin filament organization. These studies have shown that the Rho GTPases are essential for basic cellular processes, such as cell migration, contraction, and division. In this paper, we report that RhoD has a role in the organization of actin dynamics that is distinct from the roles of the better-studied Rho members Cdc42, RhoA, and Rac1. We found that RhoD binds the actin nucleation-promoting factor WASp homologue associated with actin Golgi membranes and microtubules (WHAMM), as well as the related filamin A-binding protein FILIP1. Of these two RhoD-binding proteins, WHAMM was found to bind to the Arp2/3 complex, while FILIP1 bound filamin A. WHAMM was found to act downstream of RhoD in regulating cytoskeletal dynamics. In addition, cells treated with small interfering RNAs for RhoD and WHAMM showed increased cell attachment and decreased cell migration. These major effects on cytoskeletal dynamics indicate that RhoD and its effectors control vital cytoskeleton-driven cellular processes. In agreement with this notion, our data suggest that RhoD coordinates Arp2/3-dependent and FLNa-dependent mechanisms to control the actin filament system, cell adhesion, and cell migration.

  • 36.
    Gowda, Naveen Kumar Chandappa
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Masser, Anna E.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kang, Wenjing
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Friedländer, Marc R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27, no 8, p. 1210-1219Article in journal (Refereed)
    Abstract [en]

    Cells maintain proteostasis by selectively recognizing and targeting misfolded proteins for degradation. In Saccharomyces cerevisiae, the Hsp70 nucleotide exchange factor Fes1 is essential for the degradation of chaperone-associated misfolded proteins by the ubiquitin-proteasome system. Here we show that the FES1 transcript undergoes unique 3' alternative splicing that results in two equally active isoforms with alternative C-termini, Fes1L and Fes1S. Fes1L is actively targeted to the nucleus and represents the first identified nuclear Hsp70 nucleotide exchange factor. In contrast, Fes1S localizes to the cytosol and is essential to maintain proteostasis. In the absence of Fes1S, the heat-shock response is constitutively induced at normally non-stressful conditions. Moreover, cells display severe growth defects when elevated temperatures, amino acid analogues or the ectopic expression of misfolded proteins, induce protein misfolding. Importantly, misfolded proteins are not targeted for degradation by the ubiquitin-proteasome system. These observations support the notion that cytosolic Fes1S maintains proteostasis by supporting the removal of toxic misfolded proteins by proteasomal degradation. This study provides key findings for the understanding of the organization of protein quality control mechanisms in the cytosol and nucleus.

  • 37. Graner, T.
    et al.
    Salomonsson, I.
    Wang, L.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Size separation of large proteins and protein complexes under native conditions.2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25Article in journal (Other academic)
  • 38.
    Hauser, Jannek
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Saarikettu, Juha
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Calcium regulation of myogenesis by differential calmodulin inhibition of basic helix-loop-helix transcription factors2008In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 19, no 6, p. 2509-2519Article in journal (Refereed)
    Abstract [en]

    The members of the MyoD family of basic helix-loop-helix (bHLH) transcription factors are critical regulators of skeletal muscle differentiation that function as heterodimers with ubiquitously expressed E-protein bHLH transcription factors. These heterodimers must compete successfully with homodimers of E12 and other E-proteins to enable myogenesis. Here, we show that E12 mutants resistant to Ca(2+)-loaded calmodulin (CaM) inhibit MyoD-initiated myogenic conversion of transfected fibroblasts. Ca(2+) channel blockers reduce, and Ca(2+) stimulation increases, transcription by coexpressed MyoD and wild-type E12 but not CaM-resistant mutant E12. Furthermore, CaM-resistant E12 gives lower MyoD binding and higher E12 binding to a MyoD-responsive promoter in vivo and cannot rescue myogenic differentiation that has been inhibited by siRNA against E12 and E47. Our data support the concept that Ca(2+)-loaded CaM enables myogenesis by inhibiting DNA binding of E-protein homodimers, thereby promoting occupancy of myogenic bHLH protein/E-protein heterodimers on promoters of myogenic target genes.

  • 39.
    Hellberg, Carina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Schmees, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Karlsson, Susann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Åhgren, Aive
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Activation of Protein Kinase C α Is Necessary for Sorting the PDGF β-Receptor to Rab4a-dependent Recycling2009In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 20, no 12, p. 2856-2863Article in journal (Refereed)
    Abstract [en]

    Previous studies showed that loss of the T-cell protein tyrosine phosphatase (TC-PTP) induces Rab4a-dependent recycling of the platelet-derived growth factor (PDGF) β-receptor in mouse embryonic fibroblasts (MEFs). Here we identify protein kinase C (PKC) α as the critical signaling component that regulates the sorting of the PDGF β-receptor at the early endosomes. Down-regulation of PKC abrogated receptor recycling by preventing the sorting of the activated receptor into EGFP-Rab4a positive domains on the early endosomes. This effect was mimicked by inhibition of PKCα, using myristoylated inhibitory peptides or by knockdown of PKCα with shRNAi. In wt MEFs, short-term preactivation of PKC by PMA caused a ligand-induced PDGF β-receptor recycling that was dependent on Rab4a function. Together, these observations demonstrate that PKC activity is necessary for recycling of ligand-stimulated PDGF β-receptor to occur. The sorting also required Rab4a function as it was prevented by expression of EGFP-Rab4aS22N. Preventing receptor sorting into recycling endosomes increased the rate of receptor degradation, indicating that the sorting of activated receptors at early endosomes directly regulates the duration of receptor signaling. Activation of PKC through the LPA receptor also induced PDGF β-receptor recycling and potentiated the chemotactic response to PDGF-BB. Taken together, our present findings indicate that sorting of PDGF β-receptors on early endosomes is regulated by sequential activation of PKCα and Rab4a and that this sorting step could constitute a point of cross-talk with other receptors.

  • 40. Hessle, Viktoria
    et al.
    Björk, Petra
    Sokolowski, Marcus
    de Valdivia, Gonzalez
    Silverstein, Rebecca
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Tyagi, Anu
    Maddalo, Gianluca
    Ilag, Leopold
    Helbig, Roger
    Zubarev, Roman A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Visa, Neus
    The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins2009In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 20, no 15, p. 3459-3470Article in journal (Refereed)
    Abstract [en]

    Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.

  • 41.
    Hessle, Viktoria
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Björk, Petra
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sokolowski, Marcus
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Gonzalez de Valdivia, Ernesto
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Silverstein, Rebecca
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Artemenko, Konstantin
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Tyagi, Anu
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Maddalo, Gianluca
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Ilag, Leopold
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Helbig, Roger
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Zubarev, Roman A
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins2009In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 20, no 15, p. 3459-3470Article in journal (Refereed)
    Abstract [en]

    Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.

  • 42.
    Heublein, Manfred
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Burguillos, Miguel A.
    Vögtle, F. Nora
    Teixeira, Pedro F.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Imhof, Axel
    Meisinger, Chris
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The novel component Kgd4 recruits the E3 subunit to the mitochondrial alpha-ketoglutarate dehydrogenase2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, no 21, p. 3342-3349Article in journal (Refereed)
    Abstract [en]

    The mitochondrial citric acid cycle is a central hub of cellular metabolism, providing intermediates for biosynthetic pathways and channeling electrons to the respiratory chain complexes. In this study, we elucidated the composition and organization of the multienzyme complex alpha-ketoglutarate dehydrogenase (alpha-KGDH). In addition to the three classical E1-E3 subunits, we identified a novel component, Kgd4 (Ymr31/MRPS36), which was previously assigned to be a subunit of the mitochondrial ribosome. Biochemical analyses demonstrate that this protein plays an evolutionarily conserved role in the organization of mitochondrial alpha-KGDH complexes of fungi and animals. By binding to both the E1-E2 core and the E3 subunit, Kgd4 acts as a molecular adaptor that is necessary to a form a stable alpha-KGDH enzyme complex. Our work thus reveals a novel subunit of a key citric acid-cycle enzyme and shows how this large complex is organized.

  • 43. Holmfeldt, Per
    et al.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Stenmark, Sonja
    Gullberg, Martin
    Deciphering the cellular functions of the Op18/stathmin family of microtubule-regulators by plasma membrane-targeted localization2003In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 9, p. 3716-3729Article in journal (Refereed)
  • 44. Högstrand, K
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute / Stockholm University.
    Gene conversion of major histocompatibility complex genes in the mouse spermatogenesis is a premeiotic event1997In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 8, no 12, p. 2511-2517Article in journal (Refereed)
    Abstract [en]

    The molecular genetic mechanism of gene conversion in higher eukaryotes remains unknown. We find it of considerable interest to determine when during spermatogenesis gene conversion occurs. We have therefore purified pachytene spermatocytes and haploid spermatocytes from adult mice and analyzed these fractions for the presence of gene conversion products resulting from the transfer between the major histocompatibility complex class II genes Ebd and Abk in a polymerase chain reaction assay. We have further isolated spermatogenic cells from prepubescent mice and analyzed them for the presence of the same gene conversion products. We can detect gene conversion products in testis cells as early as in 8-d-old mice where the only existing spermatogenic cells are spermatogonia. The frequency of gene conversion products remains the same as the cells reach meiosis in 18-d-old mice, and is unchanged after meiosis is completed in haploid spermatocytes. Gene conversion of this specific fragment therefore appears to be a premeiotic event and, consequently, relies on genetic mechanisms other than normal meiotic recombination.

  • 45. Immerstrand, C
    et al.
    Nilsson, H
    Lindroth, Margaretha
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Peterson, KH
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Confocal and electron microscopy of melanosome aggregation in Xenopus laevis melanophores2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, p. 2664-Conference paper (Other academic)
  • 46.
    Jarrin, Miguel
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Pandit, Tanushree
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 16, p. 3266-3274Article in journal (Refereed)
    Abstract [en]

    In embryonic and adult lenses, a balance of cell proliferation, cell cycle exit, and differentiation is necessary to maintain physical function. The molecular mechanisms regulating the transition of proliferating lens epithelial cells to differentiated primary lens fiber cells are poorly characterized. To investigate this question, we used gain- and loss-of-function analyses to modulate fibroblast growth factor (FGF) and/or bone morphogenetic protein (BMP) signals in chick lens/retina explants. Here we show that FGF activity plays a key role for proliferation independent of BMP signals. Moreover, a balance of FGF and BMP signals regulates cell cycle exit and the expression of Ccdc80 (also called Equarin), which is expressed at sites where differentiation of lens fiber cells occurs. BMP activity promotes cell cycle exit and induces Equarin expression in an FGF-dependent manner. In contrast, FGF activity is required but not sufficient to induce cell cycle exit or Equarin expression. Furthermore, our results show that in the absence of BMP activity, lens cells have increased cell cycle length or are arrested in the cell cycle, which leads to decreased cell cycle exit. Taken together, these findings suggest that proliferation, cell cycle exit, and early differentiation of primary lens fiber cells are regulated by counterbalancing BMP and FGF signals.

  • 47.
    Jidigam, Vijay
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Role of BMP signaling on cytoskeleton elements in the sensory placode invagination2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, article id P1653Article in journal (Other academic)
  • 48. Johansson, H
    et al.
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Platelets and plasma modulate oxygen radical production in neutrophils by mechanisms involving adenosine and arachidonic acid metabolites2001In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 12, p. 1415-Conference paper (Other academic)
  • 49.
    Karlsson, Susann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kowanetz, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Sandin, Åsa
    Persson, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Östman, Arne
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hellberg, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Loss of T-Cell Protein Tyrosine Phosphatase Induces Recycling of the Platelet-derived Growth Factor (PDGF) beta-Receptor but Not the PDGF {alpha}-Receptor2006In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 17, no 11, p. 4846-4855Article in journal (Refereed)
    Abstract [en]

    We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) beta-receptor. Here, we show that the increased PDGF beta-receptor phosphorylation in TC-PTP knockout (ko) mouse embryonic fibroblasts (MEFs) occurs primarily on the cell surface. The increased phosphorylation is accompanied by a TC-PTP-dependent, monensin-sensitive delay in clearance of cell surface PDGF beta-receptors and delayed receptor degradation, suggesting PDGF beta-receptor recycling. Recycled receptors could also be directly detected on the cell surface of TC-PTP ko MEFs. The effect of TC-PTP depletion was specific for the PDGF beta-receptor, because PDGF alpha-receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF alphabeta-receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF beta-receptors colocalized with Rab4a, a marker for rapid recycling. In accordance with this, transient expression of a dominant-negative Rab4a construct increased the rate of clearance of cell surface receptors on TC-PTP ko MEFs. Thus, loss of TC-PTP specifically redirects the PDGF beta-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

  • 50. Klemm, Anna H
    et al.
    Bosilj, Agneza
    Glunčic, Matko
    Pavin, Nenad
    Tolic, Iva M
    Metaphase kinetochore movements are regulated by kinesin-8 motors and microtubule dynamic instability.2018In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 29, no 11, p. 1332-1345Article in journal (Refereed)
    Abstract [en]

    During metaphase, sister chromatids are connected to microtubules extending from the opposite spindle poles via kinetochores to protein complexes on the chromosome. Kinetochores congress to the equatorial plane of the spindle and oscillate around it, with kinesin-8 motors restricting these movements. Yet, the physical mechanism underlying kinetochore movements is unclear. We show that kinetochore movements in the fission yeast Schizosaccharomyces pombe are regulated by kinesin-8-promoted microtubule catastrophe, force-induced rescue, and microtubule dynamic instability. A candidate screen showed that among the selected motors only kinesin-8 motors Klp5/Klp6 are required for kinetochore centering. Kinesin-8 accumulates at the end of microtubules, where it promotes catastrophe. Laser ablation of the spindle resulted in kinetochore movement toward the intact spindle pole in wild-type and klp5Δ cells, suggesting that kinetochore movement is driven by pulling forces. Our theoretical model with Langevin description of microtubule dynamic instability shows that kinesin-8 motors are required for kinetochore centering, whereas sensitivity of rescue to force is necessary for the generation of oscillations. We found that irregular kinetochore movements occur for a broader range of parameters than regular oscillations. Thus, our work provides an explanation for how regulation of microtubule dynamic instability contributes to kinetochore congression and the accompanying movements around the spindle center.

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