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Published 2 August 2004. doi:10.1083/jcb.200403003
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 3, 407-418
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Article

 Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by ß1 integrins

Hira Lal Goel1, Mara Fornaro4, Loredana Moro4, Natalia Teider1, Johng S. Rhim5, Michael King1, and Lucia R. Languino1,2,3,4

1 Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
2 Department Cell Biology, University of Massachusetts Medical School, Worcester, MA 01605
3 Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605
4 Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
5 Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814

Address correspondence to Lucia Languino, Dept. of Cancer Biology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Tel.: (508) 856-1606. Fax: (508) 856-3845. email: lucia.languino{at}umassmed.edu

We show here that ß1 integrins selectively modulate insulin-like growth factor type I receptor (IGF-IR) signaling in response to IGF stimulation. The ß1A 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, ß1C, 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, ß1C 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 ß1 cytodomain plays an important role in mediating ß1 integrin association with either IRS-1 or Grb2-associated binder1 (Gab1)/SH2-containing protein-tyrosine phosphate 2 (Shp2), downstream effectors of IGF-IR: specifically, ß1A associates with IRS-1 and ß1C 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.

Key Words: laminin; prostate; Gab1; IRS-1; PI 3-kinase

Abbreviations used in this paper: ß-gal, ß-galactosidase; FN, fibronectin; Gab1, Grb2-associated binder1; IGF, insulin-like growth factor; IGF-IR, IGF type 1 receptor; IRS-1, insulin receptor substrate-1; LN, laminin; PI 3-kinase, phosphatidylinositol 3-kinase; RZ, ribozyme; Shp2, SH2-containing protein-tyrosine phosphatase 2; SRB, Sulforhodamine B; tet, tetracycline.


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