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J. Biol. Chem., Vol. 280, Issue 23, 22070-22080, June 10, 2005

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The Calpain System Is Involved in the Constitutive Regulation of -Catenin Signaling Functions^*

Roberta Benetti, Tamara Copetti, Stefania Dell'Orso, Edon Melloni¶, Claudio Brancolini||, Martin Monte, and Claudio Schneider||**

From the Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, Area Science Park, Padriciano 99, 34012 Trieste, Italy, the ^¶Department of Experimental Medicine-Biochemistry Section and Centre of Excellence for Biomedical Research, Università di Genova, Viale Benedetto XV, 16132 Genova, Italy, and the ^||Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Piazzale Kolbe 4, 33100-Udine, Italy

-Catenin is a multifunctional protein serving both as a structural element in cell adhesion and as a signaling component in the Wnt pathway, regulating embryogenesis and tumorigenesis. The signaling fraction of -catenin is tightly controlled by the adenomatous polyposis coli-axin-glycogen synthase kinase 3 complex, which targets it for proteasomal degradation. It has been recently shown that Ca²⁺ release from internal stores results in nuclear export and calpain-mediated degradation of -catenin in the cytoplasm. Here we have highlighted the critical relevance of constitutive calpain pathway in the control of -catenin levels and functions, showing that small interference RNA knock down of endogenous calpain per se (i.e. in the absence of external stimuli) induces an increase in the free transcriptional competent pool of endogenous -catenin. We further characterized the role of the known calpain inhibitors, Gas2 and Calpastatin, demonstrating that they can also control levels, function, and localization of -catenin through endogenous calpain regulation. Finally we present Gas2 dominant negative (Gas2DN) as a new tool for regulating calpain activity, providing evidence that it counteracts the described effects of both Gas2 and Calpastatin on -catenin and that it works via calpain independently of the classical glycogen synthase kinase 3 and proteasome pathway. Moreover, we provide in vitro biochemical evidence showing that Gas2DN can increase the activity of calpain and that in vivo it can induce degradation of stabilized/mutated -catenin. In fact, in a context where the classical proteasome pathway is impaired, as in colon cancer cells, Gas2DN biological effects accounted for a significant reduction in proliferation and anchorage-independent growth of colon cancer.

Received for publication, February 17, 2005 , and in revised form, April 7, 2005.

^* This work was supported in part by grants from Associazione Italiana per la Ricerca sul Cancro (to C. S.). 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.

Supported by a fellowship from Fondazione Italiana per la Ricerca sul Cancro.

^** To whom correspondence should be addressed. Tel.: 39-040-398995; Fax: 39-040-398990; E-mail: schneide{at}lncib.it.

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