title: Cbl associates with Pyk2 and Src to regulate Src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion, and osteoclast motility.
abstract: The signaling events downstream of integrins that regulate cell attachment and motility are only partially understood. Using osteoclasts and transfected 293 cells, we find that a molecular complex comprising Src, Pyk2, and Cbl functions to regulate cell adhesion and motility. The activation of integrin alpha(v)beta(3) induces the [Ca(2+)](i)-dependent phosphorylation of Pyk2 Y402, its association with Src SH2, Src activation, and the Src SH3-dependent recruitment and phosphorylation of c-Cbl. Furthermore, the PTB domain of Cbl is shown to bind to phosphorylated Tyr-416 in the activation loop of Src, the autophosphorylation site of Src, inhibiting Src kinase activity and integrin-mediated adhesion. Finally, we show that deletion of c Src or c-Cbl leads to a decrease in osteoclast migration. Thus, binding of alpha(v)beta(3) integrin induces the formation of a Pyk2/Src/Cbl complex in which Cbl is a key regulator of Src kinase activity and of cell adhesion and migration. These findings may explain the osteopetrotic phenotype in the Src(-/-) mice.
authors.affiliation: Department of Cell Biology and Orthopedics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sanjay
authors.forename: A
authors.initials: A
authors.lastname: Houghton
authors.forename: L
authors.initials: L
authors.lastname: Neff
authors.forename: E
authors.initials: E
authors.lastname: DiDomenico
authors.forename: C
authors.initials: C
authors.lastname: Bardelay
authors.forename: E
authors.initials: E
authors.lastname: Antoine
authors.forename: J
authors.initials: J
authors.lastname: Levy
authors.forename: J
authors.initials: J
authors.lastname: Gailit
authors.forename: D
authors.initials: D
authors.lastname: Bowtell
authors.forename: W C
authors.initials: WC
authors.lastname: Horne
authors.forename: R
authors.initials: R
authors.lastname: Baron
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D051418:Focal Adhesion Kinase 2; D006801:Humans; D016296:Mutagenesis; D010010:Osteoclasts / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000502:physiology; D019030:Receptors, Vitronectin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases
chemical_list: D011518:Proto-Oncogene Proteins; D019030:Receptors, Vitronectin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051418:Focal Adhesion Kinase 2; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; C000631346:CSK protein, human; C067419:CBL protein, human; D002118:Calcium