Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis.
W.-C. Huang, S.-H. Chan, T.-H. Jang, J.-W. Chang, Y.-C. Ko, T.-C. Yen, S.-L. Chiang, W.-F. Chiang, T.-Y. Shieh, C.-T. Liao, et al. (2014)
Cancer Res. 74, 751-764
   Abstract »    Full Text »    PDF »
G-Protein-Coupled Receptor-2-Interacting Protein-1 Is Required for Endothelial Cell Directional Migration and Tumor Angiogenesis via Cortactin-Dependent Lamellipodia Formation.
S. Majumder, M. P. Sowden, S. A. Gerber, T. Thomas, C. K. Christie, A. Mohan, G. Yin, E. M. Lord, B. C. Berk, and J. Pang (2014)
Arterioscler Thromb Vasc Biol 34, 419-426
   Abstract »    Full Text »    PDF »
G-Protein-Coupled Receptor Kinase Interacting Protein-1 Mediates Intima Formation by Regulating Vascular Smooth Muscle Proliferation, Apoptosis, and Migration.
J. Pang, X. Xu, X. Wang, S. Majumder, J. Wang, V. A. Korshunov, and B. C. Berk (2013)
Arterioscler Thromb Vasc Biol 33, 999-1005
   Abstract »    Full Text »    PDF »
The Adaptor Protein and Arf GTPase-activating Protein Cat-1/Git-1 Is Required for Cellular Transformation.
S. M. Yoo, M. A. Antonyak, and R. A. Cerione (2012)
J. Biol. Chem. 287, 31462-31470
   Abstract »    Full Text »    PDF »
G-protein-coupled Receptor Kinase Interactor-1 (GIT1) Is a New Endothelial Nitric-oxide Synthase (eNOS) Interactor with Functional Effects on Vascular Homeostasis.
S. Liu, R. T. Premont, and D. C. Rockey (2012)
J. Biol. Chem. 287, 12309-12320
   Abstract »    Full Text »    PDF »
Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling Induced by Angiotensin II in Mice.
H. Li, Q.-Z. Tang, C. Liu, M. Moon, M. Chen, L. Yan, Z.-Y. Bian, Y. Zhang, A.-B. Wang, M. P. Nghiem, et al. (2010)
Hypertension 56, 1109-1117
   Abstract »    Full Text »    PDF »
Phosphorylation of G Protein-Coupled Receptor Kinase 2-Interacting Protein 1 Tyrosine 392 Is Required for Phospholipase C-{gamma} Activation and Podosome Formation in Vascular Smooth Muscle Cells.
J. Wang, G. Yin, P. Menon, J. Pang, E. M. Smolock, C. Yan, and B. C. Berk (2010)
Arterioscler Thromb Vasc Biol 30, 1976-1982
   Abstract »    Full Text »    PDF »
G-Protein-Coupled Receptor Kinase Interacting Protein-1 Is Required for Pulmonary Vascular Development.
J. Pang, R. Hoefen, G. S. Pryhuber, J. Wang, G. Yin, R. J. White, X. Xu, M. R. O'Dell, A. Mohan, H. Michaloski, et al. (2009)
Circulation 119, 1524-1532
   Abstract »    Full Text »    PDF »
Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity.
C. M. Hartford, S. Duan, S. M. Delaney, S. Mi, E. O. Kistner, J. K. Lamba, R. S. Huang, and M. E. Dolan (2009)
Blood 113, 2145-2153
   Abstract »    Full Text »    PDF »
GIT1 Mediates VEGF-Induced Podosome Formation in Endothelial Cells: Critical Role for PLC{gamma}.
J. Wang, Y. Taba, J. Pang, G. Yin, C. Yan, and B. C. Berk (2009)
Arterioscler Thromb Vasc Biol 29, 202-208
   Abstract »    Full Text »    PDF »
An epidermal growth factor (EGF) -dependent interaction between GIT1 and sorting nexin 6 promotes degradation of the EGF receptor.
M. E. Cavet, J. Pang, G. Yin, and B. C. Berk (2008)
FASEB J 22, 3607-3616
   Abstract »    Full Text »    PDF »
GIT1 Mediates HDAC5 Activation by Angiotensin II in Vascular Smooth Muscle Cells.
J. Pang, C. Yan, K. Natarajan, M. E. Cavet, M. P. Massett, G. Yin, and B. C. Berk (2008)
Arterioscler Thromb Vasc Biol 28, 892-898
   Abstract »    Full Text »    PDF »
G protein-coupled receptor kinase 2 positively regulates epithelial cell migration.
P. Penela, C. Ribas, I. Aymerich, N. Eijkelkamp, O. Barreiro, C. J. Heijnen, A. Kavelaars, F. Sanchez-Madrid, and F. Mayor Jr (2008)
EMBO J. 27, 1206-1218
   Abstract »    Full Text »    PDF »
Identification of an Intramolecular Interaction Important for the Regulation of GIT1 Functions.
A. Totaro, S. Paris, C. Asperti, and I. de Curtis (2007)
Mol. Biol. Cell 18, 5124-5138
   Abstract »    Full Text »    PDF »
Induction of Vascular Permeability: betaPIX and GIT1 Scaffold the Activation of Extracellular Signal-regulated Kinase by PAK.
R. Stockton, J. Reutershan, D. Scott, J. Sanders, K. Ley, and M. A. Schwartz (2007)
Mol. Biol. Cell 18, 2346-2355
   Abstract »    Full Text »    PDF »
Identification of phosphorylation sites in GIT1.
D. J. Webb, M. W. Mayhew, M. Kovalenko, M. J. Schroeder, E. D. Jeffery, L. Whitmore, J. Shabanowitz, D. F. Hunt, and A. F. Horwitz (2006)
J. Cell Sci. 119, 2847-2850
   Full Text »    PDF »
The multifunctional GIT family of proteins.
R. J. Hoefen and B. C. Berk (2006)
J. Cell Sci. 119, 1469-1475
   Abstract »    Full Text »    PDF »
Extracellular Signal-regulated Kinase Regulates Clathrin-independent Endosomal Trafficking.
S. E. Robertson, S. R. G. Setty, A. Sitaram, M. S. Marks, R. E. Lewis, and M. M. Chou (2006)
Mol. Biol. Cell 17, 645-657
   Abstract »    Full Text »    PDF »
Src and FAK Kinases Cooperate to Phosphorylate Paxillin Kinase Linker, Stimulate Its Focal Adhesion Localization, and Regulate Cell Spreading and Protrusiveness.
M. C. Brown, L. A. Cary, J. S. Jamieson, J. A. Cooper, and C. E. Turner (2005)
Mol. Biol. Cell 16, 4316-4328
   Abstract »    Full Text »    PDF »
GIT1 Is a Scaffold for ERK1/2 Activation in Focal Adhesions.
G. Yin, Q. Zheng, C. Yan, and B. C. Berk (2005)
J. Biol. Chem. 280, 27705-27712
   Abstract »    Full Text »    PDF »
Paxillin: Adapting to Change.
M. C. Brown and C. E. Turner (2004)
Physiol Rev 84, 1315-1339
   Abstract »    Full Text »    PDF »
GIT1 Mediates Thrombin Signaling in Endothelial Cells: Role in Turnover of RhoA-Type Focal Adhesions.
G. P. van Nieuw Amerongen, K. Natarajan, G. Yin, R. J. Hoefen, M. Osawa, J. Haendeler, A.J. Ridley, K. Fujiwara, V. W.M. van Hinsbergh, and B. C. Berk (2004)
Circ. Res. 94, 1041-1049
   Abstract »    Full Text »    PDF »
Scaffolds Direct Src-Specific Signaling in Response to Angiotensin II: New Roles for Cas and GIT1.
K. Natarajan, G. Yin, and B. C. Berk (2004)
Mol. Pharmacol. 65, 822-825
   Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882