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Papers In Press, published online ahead of print April 9, 2004
Molecular Biology, Massachusetts General Hospital, Boston, MA 02114
Corresponding Author: seed{at}molbio.mgh.harvard.edu
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(Gly12Val), CNK1-induced apoptosis is suppressed by a dominant inhibitor of the MST1/MST2 kinases. 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 carboxyterminal 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(Gly12Val). 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.
J. Biol. Chem, 10.1074/jbc.M401699200
Submitted on February 16, 2004
Revised on April 9, 2004
Accepted on April 9, 2004
The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death
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