The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics

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Title: The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics
Authors: Romano, David
Maccario, Helene
Doherty, Carolanne
et al.
Permanent link: http://hdl.handle.net/10197/5098
Date: 4-Mar-2013
Abstract: K-Ras is frequently mutated in human cancers. Mutant (mt) K-Ras can stimulate both oncogenic transformation and apoptosis through activation of extracellular signal-regulated kinase (ERK) and AKT pathways and the MST2 pathway, respectively. The biological outcome is determined by the balance and cross talk between these pathways. In colorectal cancer (CRC), a K-Ras mutation is negatively correlated with MST2 expression, as mt K-Ras can induce apoptosis by activating the MST2 pathway. However, wild-type (wt) K-Ras can prevent the activation of the MST2 pathway upon growth factor stimulation and enable transformation by mt K-Ras in CRC cells that express MST2. Here we have investigated the mechanism by which wt and mt K-Ras differentially regulate the MST2 pathway and MST2-dependent apoptosis. The ability of K-Ras to activate MST2 and MST2-dependent apoptosis is determined by the differential activation kinetics of mt K-Ras and wt K-Ras. Chronic activation of K-Ras by mutation or overexpression of Ras exchange factors results in the activation of MST2 and LATS1, increased MST2-LATS1 complex formation, and apoptosis. In contrast, transient K-Ras activation upon epidermal growth factor (EGF) stimulation prevents the formation of the MST2-LATS1 complex in an AKT-dependent manner. Our data suggest that the close relationship between Ras prosurvival and proapoptotic signaling is coordinated via the differential regulation of the MST2-LATS1 interaction by transient and chronic stimuli.
Type of material: Journal Article
Publisher: American Society for Microbiology
Copyright (published version): 2013 American Society for Microbiology
Keywords: Ras;Erk1/2;AKT;YAP;MST2;RASSF1
DOI: 10.1128/MCB.01414-12
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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