Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by β1 integrins

W e show here that beta(1) integrins selectively modulate insulin-like growth factor type I receptor (IGF-IR) signaling in response to IGF stimulation. The PIA integrin forms a complex with the IGF-IR and insulin receptor substrate-1 (IRS-1); this complex does not promote IGF-I mediated cell adhesion to laminin (LN), although it does support IGF-mediated cell proliferation. In contrast, beta(1C), an integrin cytoplasmic variant, increases cell adhesion to LN in response to IGF-I and its down-regulation by a ribozyme prevents IGF-mediated adhesion to LN. Moreover, beta(1C) completely prevents IGF-mediated cell proliferation and tumor growth by inhibiting IGF-IR auto-phosphorylation in response to IGF-I stimulation. Evidence is provided that the beta(1) cytodomain plays an important role in mediating P, integrin association with either IRS-1 or Grb2-associated binder1 (Gabl)/SH2-containing protein-tyrosine phosphate 2 (Shp2), downstream effectors of IGIF-IR: specifically, PIA associates with IRS-1 and beta(1C) with Gab1/Shp2. This study unravels a novel mechanism mediated by the integrin cytoplasmic domain that differentially regulates cell adhesion to LN and cell proliferation in response to IGF.