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J. Biol. Chem., Vol. 279, Issue 18, 18306-18313, April 30, 2004

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Impaired Shc, Ras, and MAPK Activation but Normal Akt Activation in FL5.12 Cells Expressing an Insulin-like Growth Factor I Receptor Mutated at Tyrosines 1250 and 1251^*

Madeline Leahy, Anthony Lyons, Darren Krause, and Rosemary O'Connor

From the Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, National University of Ireland, Cork, Ireland

The Y1250F/Y1251F mutant of the insulin-like growth factor I receptor (IGF-IR) has tyrosines 1250 and 1251 mutated to phenylalanines and is deficient in IGF-I-mediated suppression of apoptosis in FL5.12 lymphocytic cells. To address the mechanism of loss of function in this mutant we investigated signaling responses in FL5.12 cells overexpressing either a wild-type (WT) or Y1250F/Y1251F (mutant) IGF-IR. Cells expressing the mutant receptor were deficient in IGF-I-induced phosphorylation of the JNK pathway and had decreased ERK and p38 phosphorylation. IGF-I induced phosphorylation of Akt was comparable in WT and mutant expressing cells. The decreased activation of the mitogen-activated protein kinase (MAPK) pathways was accompanied by greatly decreased Ras activation in response to IGF-I. Although phosphorylation of Gab2 was similar in WT and mutant cell lines, phosphorylation of Shc on Tyr³¹³ in response to IGF-I was decreased in cells expressing the mutant receptor, as was recruitment of Grb2 and Ship to Shc. However, phosphorylation of Shc on Tyr²³⁹, the Src phosphorylation site, was normal. A role for JNK in the survival of FL5.12 cells was supported by the observation that the JNK inhibitor SP600125 suppressed IGF-I-mediated protection from apoptosis. Altogether these data demonstrate that phosphorylation of Shc, and assembly of the Shc complex necessary for activation of Ras and the MAPK pathways are deficient in cells expressing the Y1250F/Y1251F mutant IGF-IR. This would explain the loss of IGF-I-mediated survival in FL5.12 cells expressing this mutant and may also explain why this mutant IGF-IR is deficient in functions associated with cellular transformation and cell migration in fibroblasts and epithelial tumor cells.

Received for publication, August 20, 2003 , and in revised form, February 10, 2004.

^* This work was supported by grants from the Cancer Research Ireland and the Irish Health Research Board. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Queensland Institute of Medical Research, Cancer and Cell Biology Division, Signal Transduction Laboratory, 300 Herston Rd., Herston, QLD 4006, Australia.

To whom correspondence should be addressed. Tel.: 353-21-4901312; Fax: 353-21-4901382; E-mail: r.oconnor{at}ucc.ie.

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