Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins.
We show here that beta1 integrins selectively modulate insulin-like growth factor type I receptor (IGF-IR) signaling in response to IGF stimulation. The beta1A 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, beta1C, 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, beta1C 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 beta1 cytodomain plays an important role in mediating beta1 integrin association with either IRS-1 or Grb2-associated binder1 (Gab1)/SH2-containing protein-tyrosine phosphate 2 (Shp2), downstream effectors of IGF-IR: specifically, beta1A associates with IRS-1 and beta1C 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.
Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation St., Worcester 01605, USA.
Hira Lal
HL
Goel
Mara
M
Fornaro
Loredana
L
Moro
Natalia
N
Teider
Johng S
JS
Rhim
Michael
M
King
Lucia R
LR
Languino
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D019012:Integrin beta1 / Q000378:metabolism*; D007797:Laminin; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D019012:Integrin beta1; C526295:Irs1 protein, mouse; D007797:Laminin; D010750:Phosphoproteins; D011506:Proteins; D017451:Receptors, Somatomedin; D019869:Phosphatidylinositol 3-Kinases