title: Kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch in the integrin outside-in signaling circuit.
abstract: Integrin-mediated cell-extracellular matrix (ECM) adhesion is critical for control of intracellular signaling; however, the mechanisms underlying this "outside-in" signaling are incompletely understood. Here we show that depletion of kindlin-2 impairs integrin outside-in signaling. Kindlin-2 is tyrosine-phosphorylated upon cell-ECM adhesion. Furthermore, kindlin-2 binds Src in a cell-ECM adhesion-regulatable fashion. At the molecular level, the kindlin-2·Src interaction is mediated by the kindlin-2 F0 and the Src SH2 and SH3 domains. Src activation increases kindlin-2 tyrosine phosphorylation and the kindlin-2·Src interaction. Conversely, inhibition of Src reduces kindlin-2 tyrosine phosphorylation and diminishes the kindlin-2·Src interaction. Finally, disruption of the kindlin-2·Src interaction, unlike depletion of kindlin-2, impairs neither cell-ECM adhesion nor cell-ECM adhesion-induced focal adhesion kinase Tyr-397 phosphorylation. However, it markedly inhibits cell-ECM adhesion-induced paxillin tyrosine phosphorylation, cell migration, and proliferation. These results suggest that kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch downstream of focal adhesion kinase in the integrin outside-in signaling circuit, relaying signals from cell-ECM adhesion to paxillin that control cell migration and proliferation.
authors.affiliation: From the Department of Pathology, University of Pittsburgh, Pittsburgh, Pittsburgh 15261.
authors.forename: Hong
authors.initials: H
authors.lastname: Qu
authors.affiliation: From the Department of Pathology, University of Pittsburgh, Pittsburgh, Pittsburgh 15261.
authors.forename: Yizeng
authors.initials: Y
authors.lastname: Tu
authors.affiliation: the Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, and.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.affiliation: the Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.affiliation: From the Department of Pathology, University of Pittsburgh, Pittsburgh, Pittsburgh 15261, carywu@pitt.edu.
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000166:cytology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; C477322:FERMT3 protein, human; D016023:Integrins; D008565:Membrane Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D051419:Paxillin; D011994:Recombinant Proteins; C527802:kindlin-2 protein, mouse; D014443:Tyrosine; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: Cell Adhesion; Extracellular Matrix; Integrin; Kindlin-2; Paxillin; Signaling; Src; Tyrosine Phosphorylation