Publication Date:
2015-09-05
Description:
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 alpha to LAMP2-positive endomembranes in the absence of ligand, suggesting that there may be latent oncogenic potential in dysregulated endomembrane trafficking.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600465/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600465/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, Douglas B -- Zoncu, Roberto -- Root, David E -- Sabatini, David M -- Sawyers, Charles L -- 1DP2CA195761-01/CA/NCI NIH HHS/ -- AI47389/AI/NIAID NIH HHS/ -- CA092629/CA/NCI NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA155169/CA/NCI NIH HHS/ -- GM07739/GM/NIGMS NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA155169/CA/NCI NIH HHS/ -- R01 CA193837/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):211-7. doi: 10.1126/science.aaa4903. Epub 2015 Sep 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26338797" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Cell Line, Tumor
;
Gene Deletion
;
Humans
;
Immunoprecipitation
;
Lysosomal-Associated Membrane Protein 2/metabolism
;
Multiprotein Complexes/metabolism
;
Mutation
;
Neoplasms/genetics/*metabolism/pathology
;
Oncogene Proteins/genetics/*metabolism
;
Phosphatidylinositol 3-Kinases/*metabolism
;
Phosphorylation/genetics
;
Protein Transport
;
Protein-Serine-Threonine Kinases/metabolism
;
Proto-Oncogene Proteins c-akt/metabolism
;
RNA Interference
;
RNA, Small Interfering/genetics
;
Receptor, Platelet-Derived Growth Factor alpha/metabolism
;
TOR Serine-Threonine Kinases/metabolism
;
rab GTP-Binding Proteins/genetics/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
