title: Integrin-mediated cell adhesion promotes tyrosine phosphorylation of p130Cas, a Src homology 3-containing molecule having multiple Src homology 2-binding motifs.
abstract: p130Cas (Cas) has been recently identified as a 130-kDa protein that is highly phosphorylated on tyrosine residues and is stably associated with p47v-crk (v-Crk) and p60v-src (v-Src) oncogene products in cells transformed by the respective genes. Cas is a novel signaling molecule having a single Src homology (SH) 3 domain and a cluster of multiple SH2-binding motifs. While the tight association of Cas with v-Crk and v-Src is strongly suggestive of a significant role in regulating cellular transformation, the function of Cas in normal untransformed cells is totally unknown. We report here that cell adhesion to fibronectin rapidly promotes tyrosine phosphorylation of Cas in human and rat fibroblast cell lines. The response was equally induced by cell adhesion to plates coated with vitronectin, laminin, and collagen but not by cell attachment to nonspecific substrate poly-L-lysine. The kinetic profile of Cas phosphorylation was almost identical with that of tyrosine phosphorylation of focal adhesion kinase pp125FAK (Fak), which is well known to be activated subsequent to integrin-mediated cell adhesion. Adhesion-dependent Cas phosphorylation was completely inhibited by treating cells with cytochalasin D, an agent that disrupts polymerization of actin stress fibers. These results suggest that tyrosine phosphorylation of Cas is stimulated by normal cell adhesion in close association with Fak phosphorylation and the formation of actin stress fibers. In v-Src- or v-Crk-transformed cells, however, the tyrosine phosphorylation of Cas is markedly increased in an adhesion-independent manner that is insensitive to treatment with cytochalasin D. Thus, Cas plays a role in signaling pathways mediated by cell adhesion as well as by transformation. We propose that Cas may amplify and propagate integrin-mediated signals by interacting with SH2-containing molecule(s).
authors.affiliation: Third Department of Internal Medicine, University of Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nojima
authors.forename: N
authors.initials: N
authors.lastname: Morino
authors.forename: T
authors.initials: T
authors.lastname: Mimura
authors.forename: K
authors.initials: K
authors.lastname: Hamasaki
authors.forename: H
authors.initials: H
authors.lastname: Furuya
authors.forename: R
authors.initials: R
authors.lastname: Sakai
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: K
authors.initials: K
authors.lastname: Tachibana
authors.forename: C
authors.initials: C
authors.lastname: Morimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
mesh_terms: D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D050719:Crk-Associated Substrate Protein; D015638:Cytochalasin D / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D007700:Kinetics; D007797:Laminin / Q000494:pharmacology; D008970:Molecular Weight; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D050736:Oncogene Protein v-crk; D010750:Phosphoproteins; D010766:Phosphorylation; D019000:Phosphotyrosine; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D050717:Retinoblastoma-Like Protein p130; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019096:Vitronectin
chemical_list: C493841:BCAR1 protein, human; C493843:Bcar1 protein, rat; D050719:Crk-Associated Substrate Protein; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D006023:Glycoproteins; D016023:Integrins; D007797:Laminin; D050736:Oncogene Protein v-crk; D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D015682:Retroviridae Proteins, Oncogenic; D019096:Vitronectin; D019000:Phosphotyrosine; D015638:Cytochalasin D; D014443:Tyrosine; D003094:Collagen; D015688:Oncogene Protein pp60(v-src)