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Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors

Goumans, MJ; Valdimarsdottir, G; Itoh, S; Rosendahl, A; Sideras, Paschalis LU and ten Dijke, P (2002) In EMBO Journal 21(7). p.1743-1753
Abstract
The generation of mice lacking specific components of the transforming growth factor-beta (TGF-beta) signal tranduction pathway shows that TGF-beta is a key player in the development and physiology of the cardiovascular system. Both pro- and anti-angiogenic properties have been ascribed to TGF-beta, for which the molecular mechanisms are unclear. Here we report that TGF-beta can activate two distinct type I receptor/Smad signalling pathways with opposite effects. TGF-beta induces phosphorylation of Smad1/5 and Smad2 in endothelial cells and these effects can be blocked upon selective inhibition of ALK1 or ALK5 expression, respectively. Whereas the TGF-beta/ALK5 pathway leads to inhibition of cell migration and proliferation, the TGF-beta/... (More)
The generation of mice lacking specific components of the transforming growth factor-beta (TGF-beta) signal tranduction pathway shows that TGF-beta is a key player in the development and physiology of the cardiovascular system. Both pro- and anti-angiogenic properties have been ascribed to TGF-beta, for which the molecular mechanisms are unclear. Here we report that TGF-beta can activate two distinct type I receptor/Smad signalling pathways with opposite effects. TGF-beta induces phosphorylation of Smad1/5 and Smad2 in endothelial cells and these effects can be blocked upon selective inhibition of ALK1 or ALK5 expression, respectively. Whereas the TGF-beta/ALK5 pathway leads to inhibition of cell migration and proliferation, the TGF-beta/ ALK1 pathway induces endothelial cell migration and proliferation. We identified genes that are induced specifically by TGF-beta-mediated ALK1 or ALK5 activation. Id1 was found to mediate the TGF-beta/ALK1-induced (and Smad-dependent) migration, while induction of plasminogen activator inhibitor-1 by activated ALK5 may contribute to the TGF-beta-induced maturation of blood vessels. Our results suggest that TGF-beta regulates the activation state of the endothelium via a fine balance between ALK5 and ALK1 signalling. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
signal transduction, ALK, angiogenesis, Smad, TGF-beta
in
EMBO Journal
volume
21
issue
7
pages
1743 - 1753
publisher
Oxford University Press
external identifiers
  • wos:000174992000024
  • pmid:11927558
  • scopus:0037007226
ISSN
1460-2075
DOI
10.1093/emboj/21.7.1743
language
English
LU publication?
yes
id
f4d3f6cb-7b84-4014-906c-423a329c6c55 (old id 340372)
date added to LUP
2007-08-21 09:55:42
date last changed
2017-12-10 04:25:11
@article{f4d3f6cb-7b84-4014-906c-423a329c6c55,
  abstract     = {The generation of mice lacking specific components of the transforming growth factor-beta (TGF-beta) signal tranduction pathway shows that TGF-beta is a key player in the development and physiology of the cardiovascular system. Both pro- and anti-angiogenic properties have been ascribed to TGF-beta, for which the molecular mechanisms are unclear. Here we report that TGF-beta can activate two distinct type I receptor/Smad signalling pathways with opposite effects. TGF-beta induces phosphorylation of Smad1/5 and Smad2 in endothelial cells and these effects can be blocked upon selective inhibition of ALK1 or ALK5 expression, respectively. Whereas the TGF-beta/ALK5 pathway leads to inhibition of cell migration and proliferation, the TGF-beta/ ALK1 pathway induces endothelial cell migration and proliferation. We identified genes that are induced specifically by TGF-beta-mediated ALK1 or ALK5 activation. Id1 was found to mediate the TGF-beta/ALK1-induced (and Smad-dependent) migration, while induction of plasminogen activator inhibitor-1 by activated ALK5 may contribute to the TGF-beta-induced maturation of blood vessels. Our results suggest that TGF-beta regulates the activation state of the endothelium via a fine balance between ALK5 and ALK1 signalling.},
  author       = {Goumans, MJ and Valdimarsdottir, G and Itoh, S and Rosendahl, A and Sideras, Paschalis and ten Dijke, P},
  issn         = {1460-2075},
  keyword      = {signal transduction,ALK,angiogenesis,Smad,TGF-beta},
  language     = {eng},
  number       = {7},
  pages        = {1743--1753},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors},
  url          = {http://dx.doi.org/10.1093/emboj/21.7.1743},
  volume       = {21},
  year         = {2002},
}