Mutant K-Ras Activation of the Proapoptotic MST2 Pathway Is Antagonized by Wild-Type K-Ras

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Title: Mutant K-Ras Activation of the Proapoptotic MST2 Pathway Is Antagonized by Wild-Type K-Ras
Authors: Matallanas, David
Romano, David
Al-Mulla, Fahd
et al.
Permanent link: http://hdl.handle.net/10197/5096
Date: Dec-2011
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.
Type of material: Journal Article
Publisher: Elsevier
Copyright (published version): 2011 Elsevier
Keywords: K-Ras mutations;MST2 expression;colorectal cancer
DOI: 10.1016/j.molcel.2011.10.016
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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