Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts

Focal adhesion kinase (FAK) is a key mediator of integrin signaling, which has been implicated in the regulation of cell migration and cell cycle prog ression. Using chimeric molecules that fuse the focal adhesion targeting (F AT) sequence directly to several signaling molecules, we investigated the p otential role of FAK recruitments of signaling molecules to focal contacts in the regulation of cell migration and cell cycle progression. We found th at fusion of FAT to Src, the p85 subunit of phosphatidylinositol 3-kinase, Grb7 and Grb2 resulted in the efficient focal adhesion targeting of there s ignaling molecules. We showed that expression of Src-FAT, p85-FAT, or Grb7- FAT, but not Grb2-FAT, each stimulated cell migration. Interestingly, tyros ine phosphorylation of paxillin, but not p130cas, was induced by expression of Src-FAT, suggesting a potential role of paxillin in mediating stimulati on of cell migration by the chimeric molecule, In contrast, targeting of Gr b2, but not Src, p85, or Grb7, to focal contacts increased cell cycle progr ession. Biochemical analyses correlated Erk activation bg Grb2-FAT with its stimulation of cell cycle progression. Together, these results suggest tha t at least part of the role of FAK interaction with these signaling molecul es is to recruit them to focal contacts and that distinct FAK signaling com plexes are involved in the regulation of cell migration vs, cell cycle prog ression. (C) 2001 Federation of European Biochemical Societies. Published b y Elsevier Science B.V. All rights reserved.