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

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.

We thank Kevin Catt for providing the HA-tagged AT1R. We thank Geerten van Nieuw Amerongen and Megan Cavet for critical reading of the manuscript.

This work was supported by grants from the National Institutes of Health Heart Lung and Blood Institute (R01 HL49192 and R01 HL59975) to B.C.B. J.H. was supported by a grant from the Deutsche Forschungsgemeinschaft (HA 2868/1-1).