Rab1A is an mTORC1 activator and a colorectal oncogene

Cancer Cell. 2014 Nov 10;26(5):754-69. doi: 10.1016/j.ccell.2014.09.008. Epub 2014 Oct 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / physiology
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase Kinases / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Multiprotein Complexes / metabolism
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Oncogenes
  • Phosphatidylinositol 3-Kinases / metabolism
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / physiology
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • rab GTP-Binding Proteins / physiology
  • rab1 GTP-Binding Proteins / physiology*

Substances

  • Amino Acids
  • Antibiotics, Antineoplastic
  • Multiprotein Complexes
  • Saccharomyces cerevisiae Proteins
  • TORC1 protein complex, S cerevisiae
  • Transcription Factors
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • MAP Kinase Kinase Kinases
  • YPT1 protein, S cerevisiae
  • rab GTP-Binding Proteins
  • rab1 GTP-Binding Proteins
  • Sirolimus