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Molecular and Cellular Biology, August 2001, p. 5332-5345, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5332-5345.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Hic-5-Reduced Cell Spreading on Fibronectin: Competitive Effects between Paxillin and Hic-5 through Interaction with Focal Adhesion Kinase

Naoyuki Nishiya,1 Kouichi Tachibana,2,dagger Motoko Shibanuma,1 Jun-Ichi Mashimo,1 and Kiyoshi Nose1,*

Department of Microbiology, Showa University School of Pharmaceutical Sciences, Hatanodai, Tokyo, Japan,1 and Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 021152

Received 5 September 2000/Returned for modification 20 October 2000/Accepted 16 May 2001

Hic-5 is a paxillin homologue that is localized to focal adhesion complexes. Hic-5 and paxillin share structural homology and interacting factors such as focal adhesion kinase (FAK), Pyk2/CAKbeta /RAFTK, and PTP-PEST. Here, we showed that Hic-5 inhibits integrin-mediated cell spreading on fibronectin in a competitive manner with paxillin in NIH 3T3 cells. The overexpression of Hic-5 sequestered FAK from paxillin, reduced tyrosine phosphorylation of paxillin and FAK, and prevented paxillin-Crk complex formation. In addition, Hic-5-mediated inhibition of spreading was not observed in mouse embryo fibroblasts (MEFs) derived from FAK-/- mice. The activity of c-Src following fibronectin stimulation was decreased by about 30% in Hic-5-expressing cells, and the effect of Hic-5 was restored by the overexpression of FAK and the constitutively active forms of Rho-family GTPases, Rac1 V12 and Cdc42 V12, but not RhoA V14. These observations suggested that Hic-5 inhibits cell spreading through competition with paxillin for FAK and subsequent prevention of downstream signal transduction. Moreover, expression of antisense Hic-5 increased spreading in primary MEFs. These results suggested that the counterbalance of paxillin and Hic-5 expression may be a novel mechanism regulating integrin-mediated signal transduction.

* Corresponding author. Mailing address: Department of Microbiology, Showa University School of Pharmaceutical Sciences, Hatanodai, 1-5-8, Shinagawa-ku, Tokyo, Japan. Phone: 81-3-3784-8209. Fax: 81-3-3784-6850. E-mail: knose{at}pharm.showa-u.ac.jp.

dagger Present address: Laboratory of Gene Function Analysis, Institute of Molecular and Cell Biology, National Institute of Advanced Industrial Science and Technology, Central 2, Tsukuba, Ibaraki 305-8568, Japan.

Molecular and Cellular Biology, August 2001, p. 5332-5345, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5332-5345.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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