title: The differential effects of wild-type and mutated K-Ras on MST2 signaling are determined by K-Ras activation kinetics.
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.
authors: Systems Biology Ireland, University College Dublin, Dublin, Ireland.
authors: David
authors: D
authors: Romano
authors: Helene
authors: H
authors: Maccario
authors: Carolanne
authors: C
authors: Doherty
authors: Niall P
authors: NP
authors: Quinn
authors: Walter
authors: W
authors: Kolch
authors: David
authors: D
authors: Matallanas
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D011905:Genes, ras; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C411762:RASSF1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases