Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Cross-regulation between TGFβ/BMP Signalling and the metabolic LKB1 pathway
Ludwig Institute for Cancer Research, Faculty of Medicine, Uppsala University. (TGFbeta signalling)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cell signalling determines physiological responses to many cellular stimuli and environmental changes. The transforming growth factor-beta (TGFβ)/bone morphogenetic protein (BMP) signalling pathways begin by binding of ligand to the heterodimeric receptor complex, followed by activation of Smads that translocate to the nucleus to regulate transcription of genes that further mediate cellular physiology. The TGFβ/BMP pathways are very important for proper tissue development and homeostasis, thus precise spatial and temporal regulation of the signalling pathway is required and achieved by many positive and negative signalling regulators.

This thesis work identified the liver kinase B1 (LKB1) pathway as a negative regulator of TGFβ/BMP signalling pathways. In the first paper, we established LKB1 as a negative regulator of TGFβ signalling and TGFβ-induced epithelial to mesenchymal transition (EMT). LKB1 impairs Smad4 binding capacity to DNA leading to suppressed TGFβ-activated gene transcription. The second paper describes further the mechanism of LKB1 negative regulation on BMP signalling, by mediating BMP type I receptor degradation resulting in inhibition of BMP-induced cell differentiation.

Downstream of LKB1, salt inducible kinase 1 (SIK1) is a TGFβ target gene and its expression is up-regulated by Smad2/3/4-mediated gene transcription. The third paper elucidates the mechanism of SIK1 transcriptional induction via an enhancer element located 3’ of the gene and SIK1-mediated type I TGFβ receptor degradation, which requires the activity of Smad7 and of the Smurf2 ubiquitin ligase.

The fourth manuscript finds sucrose non-fermenting (SNF) 1-like kinase 2 (NUAK2) as another TGFβ target gene and its up-regulation results in modification of the mammalian target of rapamycin (mTOR) pathway that controls protein synthesis. NUAK2 cooperates with LKB1 leading to Raptor phosphorylation and inhibition of mTOR-mediated protein synthesis. Collectively, this thesis work has provided a functional link between two important signalling pathways, the metabolic LKB1 pathway and TGFβ/BMP pathway.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 793
Keyword [en]
cell signalling, TGFbeta, BMP, LKB1, AMPK
National Category
Cell Biology Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:uu:diva-178181ISBN: 978-91-554-8417-0 (print)OAI: oai:DiVA.org:uu-178181DiVA: diva2:543361
Public defence
2012-09-27, B21, Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2012-09-04 Created: 2012-07-30 Last updated: 2013-04-02Bibliographically approved
List of papers
1. Negative regulation of TGFβ signaling by the kinase LKB1 and the scaffolding protein LIP1
Open this publication in new window or tab >>Negative regulation of TGFβ signaling by the kinase LKB1 and the scaffolding protein LIP1
2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 1, 341-353 p.Article in journal (Refereed) Published
Abstract [en]

Signal transduction by the Smad pathway elicits critical biological responses to many extracellular polypeptide factors, including TGFβ and bone morphogenetic protein. Regulation of Smad signaling imparts several cytoplasmic and nuclear mechanisms, some of which entail protein phosphorylation. Previous work established a protein complex between Smad4 and the scaffolding protein LKB1-interacting protein 1 (LIP1). LKB1 is a well studied tumor suppressor kinase that regulates cell growth and polarity. Here, we analyzed the LKB1-LIP1 and the Smad4-LIP1 protein complexes and found that LIP1 can self-oligomerize. We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr(77) of its DNA-binding domain. LKB1 inhibits Smad4 from binding to either TGFβ- or bone morphogenetic protein-specific promoter sequences, which correlates with the negative regulatory effect LKB1 exerts on Smad4-dependent transcription. Accordingly, LKB1 negatively regulates TGFβ gene responses and epithelial-mesenchymal transition. Thus, LKB1 and LIP1 provide negative control of TGFβ signaling.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-145014 (URN)10.1074/jbc.M110.190660 (DOI)000285782800037 ()20974850 (PubMedID)
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2017-12-11Bibliographically approved
2. Transcriptional induction of salt-inducible kinase 1 by transforming growth factor β leads to negative regulation of type I receptor signaling in cooperation with the Smurf2 ubiquitin ligase
Open this publication in new window or tab >>Transcriptional induction of salt-inducible kinase 1 by transforming growth factor β leads to negative regulation of type I receptor signaling in cooperation with the Smurf2 ubiquitin ligase
Show others...
2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 16, 12867-12878 p.Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor β (TGFβ)1 regulates many physiological processes and requires control mechanisms to safeguard proper and timely action. We have previously described how negative regulation of TGFβ signaling is controlled by the serine/threonine kinase salt-inducible kinase (SIK) 1. SIK1 forms complexes with the TGFβ type I receptor and with the inhibitory Smad7 and downregulates the type I receptor. We now demonstrate that TGFβ induces SIK1 levels via a direct transcriptional mechanism that implicates the Smad proteins and we have mapped a putative enhancer element on the SIK1 gene. We provide evidence that the ubiquitin ligase Smurf2 forms complexes and functionally cooperates with SIK1. Both the kinase activity of SIK1 and the ubiquitin ligase activity of Smurf2 are important for proper type I receptor turnover. We also show that knockdown of endogenous SIK1 and Smurf2 enhances physiological signaling by TGFβ that leads to epithelial growth arrest. In conclusion, TGFβ induces expression of Smad7, Smurf2 and SIK1, the products of which physically and functionally interlink to control the activity of this pathway.

Keyword
Signal transduction, SIK1, Smad, Smurf, SNF1LK, TGFβ, Ubiquitin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-169792 (URN)10.1074/jbc.M111.307249 (DOI)000302903700026 ()22378783 (PubMedID)
Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2017-12-07Bibliographically approved

Open Access in DiVA

fulltext(17048 kB)2134 downloads
File information
File name FULLTEXT01.pdfFile size 17048 kBChecksum SHA-512
0b682a0f10b6d415646bacced612808af2209f1bfff74a615daa5edacb29fc9093dba3b56559290ab7fd040f21b6f9b4878439d13e42018799f4e14d79de8421
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Raja, Erna
Cell BiologyBiochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 2134 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 720 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf