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Published 21 January 2002. doi:10.1083/jcb.200108030
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© The Rockefeller University Press, 0021-9525/2002/1/377 $5.00
The Journal of Cell Biology, Volume 156, Number 2, January 21, 2002 377-388

Article

 The integrin cytoplasmic domain-associated protein ICAP-1 binds and regulates Rho family GTPases during cell spreading

Simona Degani1, Fiorella Balzac1, Mara Brancaccio1, Simona Guazzone1, Saverio Francesco Retta1, Lorenzo Silengo1, Alessandra Eva2 and Guido Tarone1

1 Department of Genetics, Biology and Biochemistry, University of Torino, 10126 Torino
2 Laboratory of Molecular Biology, Istituto G. Gaslini, 16148 Genova Quarto, Italy

Address correspondence to Guido Tarone, Dept. of Genetics, Biology, and Biochemistry, University of Torino, Via Santena 5 bis, 10126 Torino, Italy. Tel.: 39-011-670-6679. Fax: 39-011-670-6547. E-mail: guido.tarone{at}unito.it

Using two-hybrid screening, we isolated the integrin cytoplasmic domain-associated protein (ICAP-1), an interactor for the COOH terminal region of the ß1A integrin cytoplasmic domain. To investigate the role of ICAP-1 in integrin-mediated adhesive function, we expressed the full-length molecule in NIH3T3 cells. ICAP-1 expression strongly prevents NIH3T3 cell spreading on extracellular matrix. This inhibition is transient and can be counteracted by coexpression of a constitutively activated mutant of Cdc42, suggesting that ICAP-1 acts upstream of this GTPase. In addition, we found that ICAP-1 binds both to Cdc42 and Rac1 in vitro, and its expression markedly inhibits activation of these GTPases during integrin-mediated cell adhesion to fibronectin as detected by PAK binding assay. In the attempt to define the molecular mechanism of this inhibition, we show that ICAP-1 reduces both the intrinsic and the exchange factor–induced dissociation of GDP from Cdc42; moreover, purified ICAP-1 displaces this GTPase from cellular membranes. Together, these data show for the first time that ICAP-1 regulates Rho family GTPases during integrin-mediated cell matrix adhesion, acting as guanine dissociation inhibitor.

Key Words: integrins; Cdc42; Rac; ICAP-1; GDI; cytoskeleton


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