title: Paxillin phosphorylation at Ser273 localizes a GIT1-PIX-PAK complex and regulates adhesion and protrusion dynamics.
abstract: Continuous adhesion formation and disassembly (adhesion turnover) in the protrusions of migrating cells is regulated by unclear mechanisms. We show that p21-activated kinase (PAK)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover. Paxillin-S273 phosphorylation dramatically increases migration, protrusion, and adhesion turnover by increasing paxillin-GIT1 binding and promoting the localization of a GIT1-PIX-PAK signaling module near the leading edge. Mutants that interfere with the formation of this ternary module abrogate the effects of paxillin-S273 phosphorylation. PAK-dependent paxillin-S273 phosphorylation functions in a positive-feedback loop, as active PAK, active Rac, and myosin II activity are all downstream effectors of this turnover pathway. Finally, our studies led us to identify in highly motile cells a class of small adhesions that reside near the leading edge, turnover in 20-30 s, and resemble those seen with paxillin-S273 phosphorylation. These adhesions appear to be regulated by the GIT1-PIX-PAK module near the leading edge.
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Nayal
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Webb
authors.forename: Claire M
authors.initials: CM
authors.lastname: Brown
authors.forename: Erik M
authors.initials: EM
authors.lastname: Schaefer
authors.forename: Miguel
authors.initials: M
authors.lastname: Vicente-Manzanares
authors.forename: Alan Rick
authors.initials: AR
authors.lastname: Horwitz
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D022081:Cell Surface Extensions / Q000378:metabolism* / Q000648:ultrastructure; D006224:Cricetinae; D025461:Feedback, Physiological / Q000502:physiology; D005347:Fibroblasts; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D024462:Myosin Type II / Q000378:metabolism; D051419:Paxillin / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C485648:Git1 protein, rat; D020662:Guanine Nucleotide Exchange Factors; D046911:Macromolecular Substances; D051419:Paxillin; D010750:Phosphoproteins; C496063:Pxn protein, rat; D064067:Rho Guanine Nucleotide Exchange Factors; D012694:Serine; C515906:Pak1 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D024462:Myosin Type II; D020744:rac GTP-Binding Proteins