title: Paxillin kinase linker (PKL) regulates Vav2 signaling during cell spreading and migration.
abstract: The Rho family of GTPases plays an important role in coordinating dynamic changes in the cell migration machinery after integrin engagement with the extracellular matrix. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and negatively regulated by GTPase-activating proteins (GAPs). However, the mechanisms by which GEFs and GAPs are spatially and temporally regulated are poorly understood. Here the activity of the proto-oncogene Vav2, a GEF for Rac1, RhoA, and Cdc42, is shown to be regulated by a phosphorylation-dependent interaction with the ArfGAP PKL (GIT2). PKL is required for Vav2 activation downstream of integrin engagement and epidermal growth factor (EGF) stimulation. In turn, Vav2 regulates the subsequent redistribution of PKL and the Rac1 GEF β-PIX to focal adhesions after EGF stimulation, suggesting a feedforward signaling loop that coordinates PKL-dependent Vav2 activation and PKL localization. Of interest, Vav2 is required for the efficient localization of PKL and β-PIX to the leading edge of migrating cells, and knockdown of Vav2 results in a decrease in directional persistence and polarization in migrating cells, suggesting a coordination between PKL/Vav2 signaling and PKL/β-PIX signaling during cell migration.
authors.affiliation: Department of Cell and Developmental Biology, State University of New York, Upstate Medical University, Syracuse, NY 13210-2375, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Jones
authors.forename: Kazuya
authors.initials: K
authors.lastname: Machida
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Mayer
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Turner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D004815:Epidermal Growth Factor / Q000494:pharmacology; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D022502:Stress Fibers / Q000378:metabolism; D018909:src Homology Domains
chemical_list: C576606:ARHGEF7 protein, human; C430213:GIT2 protein, human; D020690:GTPase-Activating Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; D064067:Rho Guanine Nucleotide Exchange Factors; C093651:VAV2 protein, human; D004815:Epidermal Growth Factor