title: Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth.
abstract: Rheb is a Ras family GTPase, which binds to and activates mammalian target of rapamycin complex 1 (mTORC1) when GTP loaded. Recently, cancer genome sequencing efforts have identified recurrent Rheb Tyr35Asn mutations in kidney and endometrial carcinoma. Here we show that Rheb-Y35N causes not only constitutive mTORC1 activation, but sustained activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and mTORC1-independent manner, contributing to intrinsic resistance to rapamycin. Rheb-Y35N transforms NIH3T3 cells, resulting in aggressive tumor formation in xenograft nude mice, which could be suppressed by combined treatment with rapamycin and an extracellular signal-regulated kinase (ERK) inhibitor. Furthermore, Rheb-Y35N inhibits AMPKα activation in response to nutrient depletion or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), leading to attenuated phosphorylation of BRAF-S729 and retained mitogen-activated protein kinase (MAPK) activation. Finally, we demonstrate that Rheb-WT can bind AMPK to facilitate AMPK activation, whereas Rheb-Y35N competitively binds AMPK, impairing AMPK phosphorylation. In summary, our findings indicate that Rheb-Y35N is a dominantly active tumor driver that activates both mTORC1 and MAPK to promote tumor growth, suggesting a combination of mTORC1 and MAPK inhibitors may be of therapeutic value in patients whose cancers sustain this mutation.
authors.affiliation: Scientific Research Center for Translational Medicine, Department of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|School of life Science, Dalian University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Hong
authors.affiliation: School of life Science, Dalian University, Dalian, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Scientific Research Center for Translational Medicine, Department of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Department of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences Dalian, Liaoning, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Scientific Research Center for Translational Medicine, Department of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: H-L
authors.initials: HL
authors.lastname: Piao
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Department of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences Dalian, Liaoning, China.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.affiliation: Divisions of Pulmonary and Critical Care Medicine, Brigham & Women Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Scientific Research Center for Translational Medicine, Department of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|Divisions of Pulmonary and Critical Care Medicine, Brigham & Women Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009479:Neuropeptides / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D025521:Tumor Suppressor Proteins; D020928:Mitogen-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins