Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly.
The p21-activated kinase PAK is targeted to focal complexes (FCs) through interactions with the SH3 domains of the PAK-interacting exchange factor PIX and Nck. PIX is a Rac GTP exchange factor that also binds the G-protein-coupled receptor kinase-interacting protein known as GIT1. Overexpression of GIT1 in fibroblasts or epithelial cells causes a loss of paxillin from FCs and stimulates cell motility. This is due to the direct interaction of a C-terminal 125-residue domain of GIT1 with paxillin, under the regulation of PIX. In its activated state, GIT1 can promote FC disassembly independent of actin-myosin contractile events. Additionally, GIT directly couples to a key component of FCs, focal adhesion kinase (FAK), via a conserved Spa2 homology domain. We propose that GIT1 and FAK cooperate to promote motility both by directly regulating focal complex dynamics and by the activation of Rac.
Glaxo-IMCB Group, Institute of Molecular and Cell Biology, Singapore 117609, Singapore.
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D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002465:Cell Movement; D002645:Chickens; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D005982:Glutathione Transferase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008858:Microscopy, Phase-Contrast; D008954:Models, Biological; D015513:Oncogene Proteins / Q000378:metabolism; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D064067:Rho Guanine Nucleotide Exchange Factors; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D014162:Transfection; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D005656:Fungal Proteins; C485647:GIT1 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C078332:Nck protein; D015513:Oncogene Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D064067:Rho Guanine Nucleotide Exchange Factors; C065889:SPA2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005982:Glutathione Transferase; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins