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J. Biol. Chem., Vol. 280, Issue 30, 27705-27712, July 29, 2005

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GIT1 Is a Scaffold for ERK1/2 Activation in Focal Adhesions^*

Guoyong Yin, Qinlei Zheng, Chen Yan, and Bradford C. Berk

From the Center for Cardiovascular Research and Department of Medicine, University of Rochester, Rochester, New York 14642

GIT1 (G protein-coupled receptor kinase-interacting protein 1) has been shown to regulate focal adhesion disassembly. We previously reported that GIT1 associates with MEK1 and acts as a scaffold to enhance ERK1/2 activation. Here, we show that GIT1 co-localizes with ERK1/2 in focal adhesions and regulates cell migration in vascular smooth muscle cells, HEK293 cells, and HeLa cells. Immunofluorescence showed that GIT1 co-localized with phospho-ERK1/2 in focal adhesions after epidermal growth factor stimulation. Because Src is required for both GIT1 tyrosine phosphorylation and focal adhesion disassembly, we studied the effects of Src on GIT1-ERK1/2 interactions. PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) inhibited association of GIT1 with ERK1/2, and their co-localization in focal adhesions was dramatically decreased in SYF–/– cells. GIT1 small interfering RNA significantly inhibited ERK1/2 recruitment to and activation in focal adhesions. GIT1 small interfering RNA and mutated GIT1 lacking the MEK1 binding domain significantly decreased epidermal growth factor-stimulated cell spreading and migration, suggesting that GIT1-mediated events such as ERK1/2 activation are required for spreading and migration. In summary, the present study further supports a key role for GIT1 (a MEK1-binding protein) as a scaffold for signal transduction in focal adhesions.

Received for publication, March 1, 2005 , and in revised form, May 25, 2005.

^* This work was supported by National Institutes of Health Grant R01 HL63462 (to B. C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: University of Rochester, Box MED, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-273-1946; Fax: 585-273-1497; E-mail: Bradford_Berk{at}URMC.Rochester.edu.

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