Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras

Matallanas, D. et al. (2011) Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Molecular Cell, 44(6), pp. 893-906. (doi:10.1016/j.molcel.2011.10.016)

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Publisher's URL: http://dx.doi.org/10.1016/j.molcel.2011.10.016

Abstract

K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sansom, Professor Owen
Authors: Matallanas, D., Romano, D., Al-Mulla, F., O'Neill, E., Al-Ali, W., Crespo, P., Doyle, B., Nixon, C., Sansom, O., Drosten, M., Barbacid, M., and Kolch, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Cell
ISSN:1097-2765
ISSN (Online):1097-4164
Published Online:22 December 2011

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