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PIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor
1 Department of Internal Medicine and Clinical Immunology and 2 Department of Molecular Biology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawa-ku, Yokohama 236-0004 Japan
3 Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, Ibaraki 305-8575, Japan
Rho GTPases, Cdc42 and Rac1, play pivotal roles in cell migration by efficiently integrating cell-substrate adhesion and actin polymerization. Although it has been suggested that integrins stimulate these Rho GTPases via some of integrin binding proteins such as focal adhesion kinase (FAK) and paxillin, the precise molecular mechanism is largely unknown. In this study, we showed that the over-expression of RP1 corresponding to the first CH domain (CH1) of affixin, an integrin-linked kinase (ILK)-binding protein, induced a significant actin reorganization in MDCK cells by activating Cdc42/Rac1. Affixin full length and RP1 co-immunoprecipitated with 
PIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor (GEF), and they co-localized at the tips of lamellipodia in motile cells. The involvement of PIX in the RP1-induced Cdc42 activation was demonstrated by the significant dominant negative effect of a point mutant of PIX, PIX (L383R, L384S), lacking GEF activity. Our data strongly support that ILK and affixin provide a novel signalling pathway that links integrin signalling to Cdc42/Rac1 activation.
* Correspondence: E-mail: ishigats{at}med.yokohama-cu.ac.jp
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