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Mol. Cell. Biol. 24 (2): 875-885

Copyright © 2004 by the American Society for Microbiology. All rights reserved.

GIT1 Functions as a Scaffold for MEK1-Extracellular Signal-Regulated Kinase 1 and 2 Activation by Angiotensin II and Epidermal Growth Factor

Guoyong Yin, Judith Haendeler, Chen Yan, and Bradford C. Berk*

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

Received for publication 18 July 2003. Revision received 29 August 2003. Accepted for publication 21 October 2003.

Abstract: Activation of the mitogen-activated protein kinase pathway represented by extracellular signal-regulated kinases (ERK1/2) and activation of the upstream kinase (MEK1) are critical events for growth factor signal transduction. c-Src has been proposed as a common mediator for these signals in response to both G protein-coupled receptors (GPCRs) and tyrosine kinase-coupled receptors (TKRs). Here we show that the GPCR kinase-interacting protein 1 (GIT1) is a substrate for c-Src that associates with MEK1 in vascular smooth-muscle cells and human embryonic kidney 293 cells. GIT1 binding via coiled-coil domains and a Spa2 homology domain is required for sustained activation of MEK1-ERK1/2 after stimulation with angiotensin II and epidermal growth factor. We propose that GIT1 serves as a scaffold protein to facilitate c-Src-dependent activation of MEK1-ERK1/2 in response to both GPCRs and TKRs.

* Corresponding author. Mailing address: Center for Cardiovascular Research, University of Rochester, 601 Elmwood Ave., Rochester, NY 14642. Phone: (585) 275-0810. Fax: (585) 273-1497. E-mail: bradford_berk{at}urmc.rochester.edu.

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