Identification of an oncogenic RAB protein.
In a short hairpin RNA screen for genes that affect AKT phosphorylation, we identified the RAB35 small guanosine triphosphatase (GTPase)-a protein previously implicated in endomembrane trafficking-as a regulator of the phosphatidylinositol 3'-OH kinase (PI3K) pathway. Depletion of RAB35 suppresses AKT phosphorylation in response to growth factors, whereas expression of a dominant active GTPase-deficient mutant of RAB35 constitutively activates the PI3K/AKT pathway. RAB35 functions downstream of growth factor receptors and upstream of PDK1 and mTORC2 and copurifies with PI3K in immunoprecipitation assays. Two somatic RAB35 mutations found in human tumors generate alleles that constitutively activate PI3K/AKT signaling, suppress apoptosis, and transform cells in a PI3K-dependent manner. Furthermore, oncogenic RAB35 is sufficient to drive platelet-derived growth factor receptor α to LAMP2-positive endomembranes in the absence of ligand, suggesting that there may be latent oncogenic potential in dysregulated endomembrane trafficking.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Weill Cornell/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Douglas B
DB
Wheeler
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
Roberto
R
Zoncu
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
David E
DE
Root
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. sawyersc@mskcc.org sabatini@wi.mit.edu.
David M
DM
Sabatini
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. sawyersc@mskcc.org sabatini@wi.mit.edu.
Charles L
CL
Sawyers
D000483:Alleles; D045744:Cell Line, Tumor; D017353:Gene Deletion; D006801:Humans; D047468:Immunoprecipitation; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D052119:Lysosomal-Associated Membrane Protein 2; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D020796:Receptor, Platelet-Derived Growth Factor alpha; D058570:TOR Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins; C497811:LAMP2 protein, human; C000631429:PDK1 protein, human; C511183:RAB35 protein, human