p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase.
p130(Cas) (crk associated substrate) has the structural characteristics of an adapter protein, containing multiple consensus SH2 binding sites, an SH3 domain, and a proline-rich domain. The structure of p130(Cas) suggests that it may act to provide a framework for protein-protein interactions; however, as yet, its functional role in cells is unknown. In this report we show that p130(Cas) is localized to focal adhesions. We demonstrate that p130(Cas) associates both in vitro and in vivo with pp125(FAK) (focal adhesion kinase), a kinase implicated in signaling by the integrin family of cell adhesion receptors. p130(Cas) also associates with pp41/43(FRNK) (pp125(FAK)-related, non-kinase), an autonomously expressed form of pp125(FAK) composed of only the C-terminal noncatalytic domain. We show that the association of p130(Cas) with pp125(Fak) and pp41/43(FRNK) is direct, and is mediated by the binding of the SH3 domain of p130(Cas) to a proline-rich sequence present in both the C terminus of pp125(FAK) and in pp41/43(FRNK). In agreement with recent studies we show that p130(Cas) is tyrosine-phosphorylated upon integrin mediated cell adhesion. The association of p130(Cas) with pp125(FAK), a kinase which is activated upon cell adhesion, is likely to be functionally important in integrin mediated signal transduction.
Harte
M T
MT
Department of Microbiology and Cancer Center, University of Virginia, Health Sciences Center, Charlottesville, Virginia 22908, USA.
Hildebrand
J D
JD
Burnham
M R
MR
Bouton
A H
AH
Parsons
J T
JT
D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D050719:Crk-Associated Substrate Protein; D051416:Focal Adhesion Protein-Tyrosine Kinases; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D015394:Molecular Structure; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D050736:Oncogene Protein v-crk; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D018909:src Homology Domains
D015815:Cell Adhesion Molecules; D050719:Crk-Associated Substrate Protein; D016023:Integrins; D050736:Oncogene Protein v-crk; D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D015682:Retroviridae Proteins, Oncogenic; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src)