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TGFβ Signal Transduction in Endothelial Cells
Uppsala University, Units outside the University, Ludwig Institute for Cancer Research.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor β (TGFβ) is a multifunctional cytokine that is involved in many biological effects, such as proliferation, migration, differentiation and cell survival. TGFβ regulates cellular responses by binding to a heteromeric complex of type I and type II serine/threonine kinase receptors. The type I receptor, termed activin receptor-like kinase (ALK), acts downstream of the type II receptor and propagates the signal to the nucleus by phosphorylating receptor regulated Smads (R-Smads). The activated R-Smads can associate with the common partner Smad, Smad4, and this complex translocates to the nucleus where it participates in transcriptional regulation of target genes. TGFβ plays an important role in vascular morphogenesis. The aim of this study was to obtain more insight into the mechanisms by which TGFβ can act as an inhibitor or stimulator of angiogenesis Our findings show that in endothelial cells (ECs), TGFβ can activate two distinct type I receptor/Smad signalling pathways with opposite cellular responses. In most cell types, TGFβ signals via the TGFβ type I receptor, ALK5. However, ECs express a predominant endothelial type I receptor, named ALK1. Whereas the TGFβ/ALK1 signalling leads to activation, the TGFβ/ALK5 pathway results in an inhibition of the activation state. This suggests that TGFβ regulates the activation state of the endothelium via a fine balance between these two pathways. We identified genes that are specifically induced by TGFβ mediated ALK1 or ALK5 activation. Id1 was found to be the target gene of the ALK1/Smad1/5 pathway while induction of plasminogen activator inhibitor-1 was activated only by ALK5/Smad2 pathway. Furthermore, ALK1 activated ECs are highly invasive but this property is lost if Id1 expression is specifically knocked-down. ECs invasiveness is highly dependent on αv integrin binding to its extracellular matrix (ECM) protein partner and the invasion requires proteolytic cleavage of the ECM by metalloproteases (MMPs). Hence, TGFβ/ALK1/Id1 pathway may promote invasion by modulating the expression or activity of integrins and MMPs that are well known components of the ECM. Timing and duration of TGFβ signalling are important specificity determinants for its effect on cellular behaviour. After binding to ALK1, TGFβ induces a transient phosphorylation of Smad1/5 but a stable phosphorylation of Smad2 via ALK5. Our studies indicate that Smad7 is potently induced by ALK1 signalling and may recruit a PP1α/TIMAP phosphatase complex to ALK1 to dephosphorylate the receptor and thereby turning off phosphorylation resulting in a temporal activation of TGFβ/ALK1-induced Smad1/5 pathway. This mechanism enables an efficient and tightly temporally controlled activation resulting in the dominance of ALK5 upon prolonged exposure to TGFβ. Bone morphogenetic protein (BMP) is a member of the TGFβ superfamily and signals through Smad1/5. The BMP/Smad1/5 pathway was found to potently activate the endothelium. Id1 was identified as an important BMP target gene in ECs and was sufficient and necessary for BMP-induced EC migration. These studies not only provide new insights into possible molecular mechanisms that underlie activation and quiescence of ECs during physiological angiogenesis but may also explain the vascular phenotypes observed in mice and humans with perturbed TGFβ signalling pathways.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 45
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1357
Keywords [en]
Cell biology
Keywords [sv]
Cellbiologi
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-4284ISBN: 91-554-5984-6 (print)OAI: oai:DiVA.org:uu-4284DiVA, id: diva2:164704
Public defence
2004-05-25, Room C10:301, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-05-04 Created: 2004-05-04 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Balancing the activation state of the endothelium via two distinct TGFβ type I receptors.
Open this publication in new window or tab >>Balancing the activation state of the endothelium via two distinct TGFβ type I receptors.
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2002 In: The EMBO Journal, Vol. 21, no 7, p. 1743 - 1753Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91840 (URN)
Available from: 2004-05-04 Created: 2004-05-04Bibliographically approved
2. Smad7 and protein phosphatase 1α are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells
Open this publication in new window or tab >>Smad7 and protein phosphatase 1α are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells
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2006 (English)In: BMC Cell Biology, ISSN 1471-2121, E-ISSN 1471-2121, Vol. 7, p. 16-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In endothelial cells (EC), transforming growth factor-beta (TGF-beta) can bind to and transduce signals through ALK1 and ALK5. The TGF-beta/ALK5 and TGF-beta/ALK1 pathways have opposite effects on EC behaviour. Besides differential receptor binding, the duration of TGF-beta signaling is an important specificity determinant for signaling responses. TGF-beta/ALK1-induced Smad1/5 phosphorylation in ECs occurs transiently. RESULTS: The temporal activation of TGF-beta-induced Smad1/5 phosphorylation in ECs was found to be affected by de novo protein synthesis, and ALK1 and Smad5 expression levels determined signal strength of TGF-beta/ALK1 signaling pathway. Smad7 and protein phosphatase 1alpha (PP1alpha) mRNA expression levels were found to be specifically upregulated by TGF-beta/ALK1. Ectopic expression of Smad7 or PP1alpha potently inhibited TGF-beta/ALK1-induced Smad1/5 phosphorylation in ECs. Conversely, siRNA-mediated knockdown of Smad7 or PP1alpha enhanced TGF-beta/ALK1-induced signaling responses. PP1alpha interacted with ALK1 and this association was further potentiated by Smad7. Dephosphorylation of the ALK1, immunoprecipitated from cell lysates, was attenuated by a specific PP1 inhibitor. CONCLUSION: Our results suggest that upon its induction by the TGF-beta/ALK1 pathway, Smad7 may recruit PP1alpha to ALK1, and thereby control TGF-beta/ALK1-induced Smad1/5 phosphorylation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91841 (URN)10.1186/1471-2121-7-16 (DOI)16571110 (PubMedID)
Available from: 2004-05-04 Created: 2004-05-04 Last updated: 2017-12-14Bibliographically approved
3. Stimulation of Id1 Expression by Bone Morphogenetic Protein Is Sufficient and Necessary for Bone Morphogenetic Protein–Induced Activation of Endothelial Cells
Open this publication in new window or tab >>Stimulation of Id1 Expression by Bone Morphogenetic Protein Is Sufficient and Necessary for Bone Morphogenetic Protein–Induced Activation of Endothelial Cells
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2002 In: Circulation, Vol. 106, no 17, p. 2263-2270Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91842 (URN)
Available from: 2004-05-04 Created: 2004-05-04Bibliographically approved
4. Opposing Actions of TGFβ Signalling via ALK1 or ALK5 on Cord-like Network Formation and Invasion of Endothelial Cells
Open this publication in new window or tab >>Opposing Actions of TGFβ Signalling via ALK1 or ALK5 on Cord-like Network Formation and Invasion of Endothelial Cells
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91843 (URN)
Available from: 2004-05-04 Created: 2004-05-04 Last updated: 2010-01-13Bibliographically approved

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