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J. Biol. Chem., Vol. 283, Issue 33, 22826-22837, August 15, 2008

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The Copper Binding Domain of SPARC Mediates Cell Survival in Vitro via Interaction with Integrin β1 and Activation of Integrin-linked Kinase^*

Matt S. Weaver, Gail Workman, and E. Helene Sage¹

From the Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101-2795 and Department of Biological Structure, University of Washington, Seattle, Washington 98195

Secreted protein acidic and rich in cysteine (SPARC) is important for the normal growth and maintenance of the murine lens. SPARC-null animals develop cataracts associated with a derangement of the lens capsule basement membrane and alterations in lens fiber morphology. Cellular stress and disregulation of apoptotic pathways within lens epithelial cells (LEC) are linked to cataract formation. To identify molecular targets of SPARC that are linked to this disorder, we stressed wild-type (WT) and SPARC-null LEC by serum deprivation or exposure to tunicamycin. SPARC enhanced signaling by integrin-linked kinase (ILK), a serine/threonine kinase known to enhance cell survival in vitro. In response to stress, an ILK-dependent decrease in apoptosis was observed in WT relative to SPARCg-null LEC. Co-immunoprecipitation and cross-linking of cell lysates revealed enhanced levels of a SPARC-integrin β1 complex during stress. Competition with monoclonal antibodies and peptides indicated that the copper binding domain of SPARC is required for SPARC-mediated response to stress. Inhibiting the binding and/or activity of ILK, integrin β1, or SPARC resulted in increased apoptosis of stressed LEC. We conclude that SPARC protects cells from stress-induced apoptosis in vitro via an interaction with integrin β1 heterodimers that enhances ILK activation and pro-survival activity.

Received for publication, August 8, 2007 , and in revised form, May 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM40711 and EY07031 (T32 to M. W.). 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.

¹ To whom correspondence should be addressed: 1201 Ninth Ave., Seattle, WA 98101-2795; Fax: 206-341-1375; E-mail: hsage{at}benaroyaresearch.org.

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