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Gab1 contributes to cytoskeletal reorganization and chemotaxis in response to platelet-derived growth factor.

Kallin, Anders; Demoulin, Jean-Baptiste; Nishida, Keigo; Hirano, Toshio; Rönnstrand, Lars LU and Heldin, Carl-Henrik (2004) In Journal of Biological Chemistry 279(17). p.17897-17904
Abstract
Gab1 is a scaffolding/docking protein that has been suggested to play a role in signal transduction downstream of certain plasma membrane receptors, including platelet-derived growth factor (PDGF) receptors. We found that PDGF induced a rapid Gab1 phosphorylation, which depended on the recruitment of Grb2, indicating that Grb2 acts as a bridge between Gab1 and the PDGF -receptor. PDGF also enhanced the binding of Gab1 to the phosphatase SHP-2, but not to p85. To further study the role of Gab1 in PDGF signaling, we transfected porcine aortic endothelial cells with a doxycycline-inducible Gab1 construct. Increased Gab1 expression enhanced the recruitment and activation of SHP-2, as well as the phosphorylation of the mitogen-activated protein... (More)
Gab1 is a scaffolding/docking protein that has been suggested to play a role in signal transduction downstream of certain plasma membrane receptors, including platelet-derived growth factor (PDGF) receptors. We found that PDGF induced a rapid Gab1 phosphorylation, which depended on the recruitment of Grb2, indicating that Grb2 acts as a bridge between Gab1 and the PDGF -receptor. PDGF also enhanced the binding of Gab1 to the phosphatase SHP-2, but not to p85. To further study the role of Gab1 in PDGF signaling, we transfected porcine aortic endothelial cells with a doxycycline-inducible Gab1 construct. Increased Gab1 expression enhanced the recruitment and activation of SHP-2, as well as the phosphorylation of the mitogen-activated protein kinases Erk and p38 by PDGF. Gab1 expression also enhanced the formation of lamellipodia and cellular protrusions. In Gab1-deficient mouse embryonic fibroblasts, the same phenotype was induced by restoring the expression of wild-type Gab1, but not a mutant Gab1 that was unable to associate with SHP-2. These effects of PDGF on the actin cytoskeleton were not altered by the inhibition of p38 or Erk, but could be blocked by a dominant-negative form of Rac (Asn17). Finally, Gab1-deficient fibroblasts showed a decreased chemotactic response toward gradients of PDGF as compared with wild-type cells. In conclusion, Gab1 plays a selective role in the regulation of the mitogen-activated protein kinases Erk and p38 downstream of the PDGF -receptor, and contributes to cytoskeletal reorganization and chemotaxis in response to PDGF. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
279
issue
17
pages
17897 - 17904
publisher
ASBMB
external identifiers
  • wos:000220870400123
  • scopus:2342418250
ISSN
1083-351X
DOI
10.1074/jbc.M312996200
language
English
LU publication?
no
id
15cec1b0-ad73-484f-8a32-e03c242f92db (old id 121769)
date added to LUP
2007-07-25 14:36:18
date last changed
2017-03-05 03:27:37
@article{15cec1b0-ad73-484f-8a32-e03c242f92db,
  abstract     = {Gab1 is a scaffolding/docking protein that has been suggested to play a role in signal transduction downstream of certain plasma membrane receptors, including platelet-derived growth factor (PDGF) receptors. We found that PDGF induced a rapid Gab1 phosphorylation, which depended on the recruitment of Grb2, indicating that Grb2 acts as a bridge between Gab1 and the PDGF -receptor. PDGF also enhanced the binding of Gab1 to the phosphatase SHP-2, but not to p85. To further study the role of Gab1 in PDGF signaling, we transfected porcine aortic endothelial cells with a doxycycline-inducible Gab1 construct. Increased Gab1 expression enhanced the recruitment and activation of SHP-2, as well as the phosphorylation of the mitogen-activated protein kinases Erk and p38 by PDGF. Gab1 expression also enhanced the formation of lamellipodia and cellular protrusions. In Gab1-deficient mouse embryonic fibroblasts, the same phenotype was induced by restoring the expression of wild-type Gab1, but not a mutant Gab1 that was unable to associate with SHP-2. These effects of PDGF on the actin cytoskeleton were not altered by the inhibition of p38 or Erk, but could be blocked by a dominant-negative form of Rac (Asn17). Finally, Gab1-deficient fibroblasts showed a decreased chemotactic response toward gradients of PDGF as compared with wild-type cells. In conclusion, Gab1 plays a selective role in the regulation of the mitogen-activated protein kinases Erk and p38 downstream of the PDGF -receptor, and contributes to cytoskeletal reorganization and chemotaxis in response to PDGF.},
  author       = {Kallin, Anders and Demoulin, Jean-Baptiste and Nishida, Keigo and Hirano, Toshio and Rönnstrand, Lars and Heldin, Carl-Henrik},
  issn         = {1083-351X},
  language     = {eng},
  number       = {17},
  pages        = {17897--17904},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Gab1 contributes to cytoskeletal reorganization and chemotaxis in response to platelet-derived growth factor.},
  url          = {http://dx.doi.org/10.1074/jbc.M312996200},
  volume       = {279},
  year         = {2004},
}