title: Rab1A is an mTORC1 activator and a colorectal oncogene.
abstract: Amino acid (AA) is a potent mitogen that controls growth and metabolism. Here we describe the identification of Rab1 as a conserved regulator of AA signaling to mTORC1. AA stimulates Rab1A GTP binding and interaction with mTORC1 and Rheb-mTORC1 interaction in the Golgi. Rab1A overexpression promotes mTORC1 signaling and oncogenic growth in an AA- and mTORC1-dependent manner. Conversely, Rab1A knockdown selectively attenuates oncogenic growth of Rab1-overexpressing cancer cells. Moreover, Rab1A is overexpressed in colorectal cancer (CRC), which is correlated with elevated mTORC1 signaling, tumor invasion, progression, and poor prognosis. Our results demonstrate that Rab1 is an mTORC1 activator and an oncogene and that hyperactive AA signaling through Rab1A overexpression drives oncogenesis and renders cancer cells prone to mTORC1-targeted therapy.
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Janice D
authors.initials: JD
authors.lastname: Thomas
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA; Department of Gastroenterology, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Cellular and Molecular Pharmacology Graduate Program, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Yue-Hua
authors.initials: YH
authors.lastname: Wei
authors.affiliation: Cellular and Molecular Pharmacology Graduate Program, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Jun-Hung
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Cellular and Molecular Pharmacology Graduate Program, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Morris
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA; Sun Yat-Sen University Cancer Center, National Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA; Sun Yat-Sen University Cancer Center, National Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: zhengst@cinj.rutgers.edu.
authors.forename: X F Steven
authors.initials: XF
authors.lastname: Zheng
mesh_terms: D000596:Amino Acids / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D020691:rab GTP-Binding Proteins / Q000502:physiology; D020761:rab1 GTP-Binding Proteins / Q000502:physiology*
chemical_list: D000596:Amino Acids; D000903:Antibiotics, Antineoplastic; D020930:MAP Kinase Kinase Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D029701:Saccharomyces cerevisiae Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D020691:rab GTP-Binding Proteins; D020761:rab1 GTP-Binding Proteins; C561842:TORC1 protein complex, S cerevisiae; C060755:YPT1 protein, S cerevisiae