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Published online 5 March 2001. doi:10.1083/jcb.152.5.971
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© The Rockefeller University Press, 0021-9525/2001//971 $5.00
The Journal of Cell Biology, Volume 152, Number 5, , 2001 971-984

Original Article

Regulation of Cdc42 Gtpase by Proline-Rich Tyrosine Kinase 2 Interacting with Psgap, a Novel Pleckstrin Homology and Src Homology 3 Domain Containing Rhogap Protein



Xiu-Rong Rena,c, Quan-Sheng Dua, Yang-Zhong Huangb, Shi-Zhou Aoc, Lin Meib, and Wen-Cheng Xionga

a Department of Pathology and Cell Adhesion and Matrix Center, Pathology, and Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, Alabama 35294
b Departments of Neurobiology, Pathology, and Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, Alabama 35294
c Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294.(205) 975-9927(205) 975-7138

wxiong{at}path.uab.edu

Proline-rich tyrosine kinase 2 (PYK2), a tyrosine kinase structurally related to focal adhesion kinase (FAK), is implicated in regulating cytoskeletal organization. However, mechanisms by which PYK2 participates in and regulates cytoskeletal organization remain largely unknown. Here we report identification of PSGAP, a novel protein that interacts with PYK2 and FAK and contains multiple domains including a pleckstrin homology domain, a rhoGTPase-activating protein domain, and a Src homology 3 domain. PYK2 interacts with PSGAP Src homology 3 domain via the carboxyl-terminal proline-rich sequence. PSGAP is able to increase GTPase activity of CDC42 and RhoA in vitro and in vivo. Remarkably, PYK2, but not FAK, can activate CDC42 via inhibition of PSGAP-mediated GTP hydrolysis of CDC42. Moreover, PSGAP is localized at cell periphery in fibroblasts in a pleckstrin homology domain–dependent manner. Over expression of PSGAP in fibroblasts results in reorganization of cytoskeletal structures and changes of cellular morphology, which requires rhoGTPase-activating activity. Taken together, our results suggest that PSGAP is a signaling protein essential for PYK2 regulation of cytoskeletal organization via Rho family GTPases.

Key Words: proline-rich tyrosine kinase 2 • focal adhesion kinase • CDC42 • rhoGAP • PSGAP

© 2001 The Rockefeller University Press

Abbreviations used in this paper: AD, activation domain; β-Gal, β-galactosidase; FAK, focal adhesion kinase; GAP, GTPase-activating protein; GST, glutathione-S-transferase; PBD, p21-binding domain of PAK1; PH, pleckstrin homology; PYK2, proline-rich tyrosine kinase 2; RBD, p21-binding domain of rhotekin; SH3, Src homology 3.


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