title: Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth.
abstract: KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors.
authors.affiliation: Authors' Affiliations: Departament de Biologia Cel·lular, Immunologia i Neurociències, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona; Hereditary Cancer Program, Translational Research Laboratory, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Gran Via 199-203, 08907- L'Hospitalet de Llobregat, Llobregat; Servei d'Anatomia Patològica i Institut de Recerca Biomèdica de Lleida, Lleida, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Barceló
authors.forename: Noelia
authors.initials: N
authors.lastname: Paco
authors.forename: Mireia
authors.initials: M
authors.lastname: Morell
authors.forename: Blanca
authors.initials: B
authors.lastname: Alvarez-Moya
authors.forename: Neus
authors.initials: N
authors.lastname: Bota-Rabassedas
authors.forename: Montserrat
authors.initials: M
authors.lastname: Jaumot
authors.forename: Felip
authors.initials: F
authors.lastname: Vilardell
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capella
authors.forename: Neus
authors.initials: N
authors.lastname: Agell
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D012694:Serine / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins