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J. Biol. Chem., Vol. 279, Issue 28, 29247-29254, July 9, 2004

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The Scaffold Protein CNK1 Interacts with the Tumor Suppressor RASSF1A and Augments RASSF1A-induced Cell Death^*

From the ^aDepartment of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, ^bDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02215, ^cDiscovery Translation Unit, The Buck Institute for Age Research, Novato, California 94945, ^fGastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, ^gDepartment of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, and ⁱDepartment of Biology, City of Hope Medical Center, Duarte, California 91010

The connector enhancer of KSR (CNK) is a multidomain scaffold protein discovered in Drosophila, where it is necessary for Ras activation of the Raf kinase. Recent studies have shown that CNK1 also interacts with RalA and Rho and participates in some aspects of signaling by these GTPases. Herein we demonstrate a novel aspect of CNK1 function, i.e. reexpression of CNK1 suppresses tumor cell growth and promotes apoptosis. As shown previously for apoptosis induced by Ki-Ras(G12V), CNK1-induced apoptosis is suppressed by a dominant inhibitor of the mammalian sterile 20 kinases 1 and (MST1/MST2). Immunoprecipitates of MST1 endogenous to LoVo colon cancer cells contain endogenous CNK1; however, no association of these two polypeptides can be detected in a yeast two-hybrid assay. CNK1 does, however, bind directly to the RASSF1A and RASSF1C polypeptides, constitutive binding partners of the MST1/2 kinases. Deletion of the MST1 carboxyl-terminal segment that mediates its binding to RASSF1A/C eliminates the association of MST1 with CNK1. Coexpression of CNK1 with the tumor suppressive isoform, RASSF1A, greatly augments CNK1-induced apoptosis, whereas the nonsuppressive RASSF1C isoform is without effect on CNK1-induced apoptosis. Overexpression of CNK1-(1–282), a fragment that binds RASSF1A but is not proapoptotic, blocks the apoptosis induced by CNK1 and by Ki-Ras(G12V). Thus, in addition to its positive role in the proliferative outputs of active Ras, the CNK1 scaffold protein, through its binding of a RASSF1A·MST complex, also participates in the proapoptotic signaling initiated by active Ras.

Received for publication, February 16, 2004

^* This work was supported by National Institutes of Health grants (to B. S., G. P. P., and J. A.) and by Center for Inflammatory Bowel Disease, CCFA, and Department of Surgery grants (to R. J. X.). 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.

^d These authors contributed equally to this work.

^e Supported by the Damon Runyon Cancer Research Fund.

^h Supported by a grant from the American Bioscience Institute to the Buck Institute.

^j To whom correspondence should be addressed: Dept. of Molecular Biology, Massachusetts General Hospital, 50 Blossom St., Boston, MA 02114. Tel.: 617-726-5975; Fax: 617-726-5962; E-mail: seed{at}molbio.mgh.harvard.edu.

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