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Gab1 Contributes to Cytoskeletal Reorganization and Chemotaxis in Response to Platelet-derived Growth Factor

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Kallin, Anders [UCL] Demoulin, Jean-Baptiste [UCL] Nishida, Keigo Hirano, Toshio Rönnstrand, Lars Heldin, Carl-Henrik

Gab1 is a scaffolding/docking protein that has been suggested to play a role in signal transduction down-stream 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 β-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 β-receptor, and contributes to cytoskeletal reorganization and chemotaxis in response to PDGF.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2004
Language Anglais
Journal information "Journal of Biological Chemistry" - Vol. 279, no. 17, p. 17897-17904 (2004)
Peer reviewed yes
Publisher American Society for Biochemistry and Molecular Biology, Inc. ((United States) Baltimore, MD)
issn 0021-9258
e-issn 1083-351X
Publication status Publié
Affiliations UCL - SSS/DDUV - Institut de Duve
UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique
Links
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Bibliographic reference Kallin, Anders ; Demoulin, Jean-Baptiste ; Nishida, Keigo ; Hirano, Toshio ; Rönnstrand, Lars ; et. al. Gab1 Contributes to Cytoskeletal Reorganization and Chemotaxis in Response to Platelet-derived Growth Factor. In: Journal of Biological Chemistry, Vol. 279, no. 17, p. 17897-17904 (2004)
Permanent URL http://hdl.handle.net/2078.1/145453