αvβ3 Integrins and Pyk2 Mediate Insulin-Like Growth Factor I Activation of Src and Mitogen-Activated Protein Kinase in 3T3-L1 Cells

The Endocrine Society - Tập 19 Số 7 - Trang 1859-1867 - 2005
H Sekimoto1, Jodi Eipper-Mains1, Sunthorn Pond‐Tor1, Charlotte M. Boney1
1Department of Pediatrics, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island 02903

Tóm tắt

AbstractIGF-I stimulates cell growth through interaction of the IGF receptor with multiprotein signaling complexes. However, the mechanisms of IGF-I receptor-mediated signaling are not completely understood. We have previously shown that IGF-I-stimulated 3T3-L1 cell proliferation is dependent on Src activation of the ERK-1/2 MAPK pathway. We hypothesized that IGF-I activation of the MAPK pathway is mediated through integrin activation of Src-containing signaling complexes. The disintegrin echistatin decreased IGF-I phosphorylation of Src and MAPK, and blocking antibodies to αv and β3 integrin subunits inhibited IGF-I activation of MAPK, suggesting that αvβ3 integrins mediate IGF-I mitogenic signaling. IGF-I increased ligand binding to αvβ3 as detected by immunofluorescent staining of ligand-induced binding site antibody and stimulated phosphorylation of the β3 subunit, consistent with inside-out activation of αvβ3 integrins. IGF-I increased tyrosine phosphorylation of the focal adhesion kinase (FAK) Pyk2 (calcium-dependent proline-rich tyrosine kinase-2) to a much greater extent than FAK, and increased association of Src with Pyk2 but not FAK. The intracellular calcium chelator BAPTA prevented IGF-I phosphorylation of Pyk2, Src, and MAPK, suggesting that IGF-I activation of Pyk2 is calcium dependent. Transient transfection with a dominant-negative Pyk2, which lacks the autophosphorylation and Src binding site, decreased IGF-I activation of MAPK, but no inhibition was seen with transfected wild-type Pyk2. These results indicate that IGF-I signaling to MAPK is dependent on inside-out activation of αvβ3 integrins and integrin-facilitated multiprotein complex formation involving Pyk2 activation and association with Src.

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The Endocrine Society

Tập 19 Số 7

1859-1867

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