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ß_1A Integrin Expression Is Required for Type 1 Insulin-Like Growth Factor Receptor Mitogenic and Transforming Activities and Localization to Focal Contacts

¹ Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts; ² Cancer Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; and ³ Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Lucia R. Languino, Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-1606; Fax: 508-856-3845; E-mail: lucia.languino{at}umassmed.edu.

The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of ß_1A integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate ß_1A, we show that ß_1A expression is required for IGF-IR–mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of ß_1A and of IGF-IR was studied. ß_1A and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of ß_1A, the levels of ß_1C, a ß₁ cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a ß_1C downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of ß_1A, ß_1C, and Gab1 deregulation in prostate cancer, we investigated whether expression of either ß₁ variant in ß₁-null cells affected IGF-IR localization. We found that IGF-IR and ß_1A were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of ß_1C, IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that ß₁ integrins and IGF-IR are concurrently deregulated and that expression of ß₁ integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies.

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