Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines.
Integrin-mediated cell adhesion cooperates with growth factor receptors in the control of cell proliferation, cell survival, and cell migration. One mechanism to explain these synergistic effects is the ability of integrins to induce phosphorylation of growth factor receptors, for instance the epidermal growth factor (EGF) receptor. Here we define some aspects of the molecular mechanisms regulating integrin-dependent EGF receptor phosphorylation. We show that in the early phases of cell adhesion integrins associate with EGF receptors on the cell membrane in a macromolecular complex including the adaptor protein p130Cas and the c-Src kinase, the latter being required for adhesion-dependent assembly of the macromolecular complex. We also show that the integrin cytoplasmic tail, c-Src kinase, and the p130Cas adaptor protein are required for phosphorylation of EGF receptor in response to integrin-mediated adhesion. We show that integrins induce phosphorylation of EGF receptor on tyrosine residues 845, 1068, 1086, and 1173, but not on residue 1148, a major site of phosphorylation in response to EGF. In addition we find that integrin-mediated adhesion increases the amount of EGF receptor expressed on the cell surface. Therefore these data indicate that integrin-mediated adhesion induces assembly of a macromolecular complex containing c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosine residues.
Moro
Laura
L
Dipartimento di Scienze Mediche, Università del Piemonte Orientale, Novara 28100, Italy.
Dolce
Laura
L
Cabodi
Sara
S
Bergatto
Elena
E
Boeri Erba
Elisabetta
E
Smeriglio
Monica
M
Turco
Emilia
E
Retta
Saverio Francesco
SF
Giuffrida
Maria Gabriella
MG
Venturino
Mascia
M
Godovac-Zimmermann
Jasminka
J
Conti
Amedeo
A
Schaefer
Erik
E
Beguinot
Laura
L
Tacchetti
Carlo
C
Gaggini
Paolo
P
Silengo
Lorenzo
L
Tarone
Guido
G
Defilippi
Paola
P
D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion; D002460:Cell Line; D050719:Crk-Associated Substrate Protein; D066246:ErbB Receptors / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D016023:Integrins; D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D019061:src-Family Kinases; C000631346:CSK protein, human