title: Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras.
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.
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Matallanas
authors.forename: David
authors.initials: D
authors.lastname: Romano
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.forename: Eric
authors.initials: E
authors.lastname: O'Neill
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Ali
authors.forename: Piero
authors.initials: P
authors.lastname: Crespo
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.forename: Owen
authors.initials: O
authors.lastname: Sansom
authors.forename: Matthias
authors.initials: M
authors.lastname: Drosten
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D000099317:Hippo Kinases
chemical_list: D050505:Mutant Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C097835:STK3 protein, human; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse