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J. Biol. Chem., Vol. 279, Issue 24, 25149-25156, June 11, 2004

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Caspase-mediated Cleavage of Insulin Receptor Substrate^*

Kirsty A. Green, Matthew J. Naylor, Emma T. Lowe, Pengbo Wang, Emma Marshman, and Charles H. Streuli

From the School of Biological Sciences, University of Manchester, Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom

Apoptosis is an important mechanism for maintaining tissue homeostasis. The efficient induction and execution of apoptosis are essential for cell clearance in specific developmental situations. Insulin-like growth factor (IGF)-I is a survival factor for epithelial cells in the mammary gland, and its withdrawal or inhibition leads to apoptosis. In this paper we describe a novel mechanism that may lead to suppression of an IGF-I-mediated signaling pathway through cleavage of insulin receptor substrate (IRS). During the process of forced weaning, when mammary epithelial cells rapidly enter apoptosis in vivo, IRS-1 and IRS-2 disappear. We have used cultured mammary epithelial cells to demonstrate that IRS removal can be mediated through the action of caspase 10. Caspase 10 activation and IRS-1 cleavage are regulated by a MKK1-signaling pathway but not by a phosphatidylinositol-3 kinase pathway nor by the extracellular proapoptotic ligands FasL, tumor necrosis factor--related apoptosis-inducing ligand (TRAIL), or transforming growth factor-3. In addition we show that the loss of IRS-1 after MKK1 inhibition prevents IGF-mediated phosphorylation of FKHRL1.

Received for publication, March 3, 2004

^* This work was supported by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council. 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.

To whom correspondence should be addressed. Tel.: 44-161-275-5576; Fax: 44-161-275-1505; E-mail: cstreuli{at}man.ac.uk.

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