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Molecular and Cellular Biology, November 2005, p. 9700-9712, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9700-9712.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Integrin {alpha}4ß1 Promotes Focal Adhesion Kinase-Independent Cell Motility via {alpha}4 Cytoplasmic Domain-Specific Activation of c-Src{ddagger}

Datsun A. Hsia ,1,{dagger},§ Ssang-Taek Lim,1,{dagger} Joie A. Bernard-Trifilo,1,{dagger} Satyajit K. Mitra,1 Sakae Tanaka,2 Jeroen den Hertog,3 Daniel N. Streblow,4 Dusko Ilic,5 Mark H. Ginsberg,6 and David D. Schlaepfer1*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037,1 Department of Orthopedic Surgery, University of Tokyo, Tokyo, Japan,2 Hubrecht Laboratory, Institute for Developmental Biology, Utrecht, The Netherlands,3 Oregon Health Sciences University, Portland, Oregon 97201,4 Department of Stomatology, University of California, San Francisco, California 94143,5 Department of Medicine, University of California, San Diego, California 920936

Received 10 May 2005/ Returned for modification 1 July 2005/ Accepted 5 August 2005

The fibronectin binding integrins {alpha}5ß1 and {alpha}4ß1 generate signals pivotal for cell migration through distinct yet undefined mechanisms. For {alpha}5ß1, ß1-mediated activation of focal adhesion kinase (FAK) promotes c-Src recruitment to FAK and the formation of a FAK-Src signaling complex. Herein, we show that FAK expression is essential for {alpha}5ß1-stimulated cell motility and that exogenous expression of human {alpha}4 in FAK-null fibroblasts forms a functional {alpha}4ß1 receptor that promotes robust cell motility equal to the {alpha}5ß1 stimulation of wild-type and FAK-reconstituted fibroblasts. {alpha}4ß1-stimulated FAK-null cell spreading and motility were dependent on the integrity of the {alpha}4 cytoplasmic domain, independent of direct paxillin binding to {alpha}4, and were not affected by PRNK expression, a dominant-negative inhibitor of Pyk2. {alpha}4 cytoplasmic domain-initiated signaling led to a ~4-fold activation of c-Src which did not require paxillin binding to {alpha}4. Notably, {alpha}4-stimulated cell motility was inhibited by catalytically inactive receptor protein-tyrosine phosphatase {alpha} overexpression and blocked by the p50Csk phosphorylation of c-Src at Tyr-529. {alpha}4ß1-stimulated cell motility of triple-null Src–/–, c-Yes–/–, and Fyn–/– fibroblasts was dependent on c-Src reexpression that resulted in p130Cas tyrosine phosphorylation and Rac GTPase loading. As p130Cas phosphorylation and Rac activation are common downstream targets for {alpha}5ß1-stimulated FAK activation, our results support the existence of a novel {alpha}4 cytoplasmic domain connection leading to c-Src activation which functions as a FAK-independent linkage to a common motility-promoting signaling pathway.

* Corresponding author. Mailing address: The Scripps Research Institute, Department of Immunology, IMM21, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8207. Fax: (858) 784-8289. E-mail: dschlaep{at}scripps.edu.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} D.A.H., S.-T.L., and J.A.B.-T. contributed equally to this work.

§ Present address: Graduate Program in Biomedical Sciences, University of California, Davis, Calif.

Molecular and Cellular Biology, November 2005, p. 9700-9712, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9700-9712.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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