Constitutively active Rheb induces oncogenic transformation.
Rheb (Ras-homolog enriched in brain) is a component of the phosphatidylinositol 3-kinase (PI3K) target of rapamycin (TOR) signaling pathway, functioning as a positive regulator of TOR. Constitutively active mutants of Rheb induce oncogenic transformation in cell culture. The transformed cells are larger and contain more protein than their normal counterparts. They show constitutive phosphorylation of the ribosomal protein S6 kinase and the eukaryotic initiation factor 4E-binding protein 1, two downstream targets of TOR. The TOR-specific inhibitor rapamycin strongly interferes with transformation induced by constitutively active Rheb, suggesting that TOR activity is essential for the oncogenic effects of mutant Rheb. Rheb-induced transformation is also dependent on a C-terminal farnesylation signal that mediates localization to a cellular membrane. An engineered N-terminal myristylation signal can substitute for the farnesylation. Immunofluorescence localizes wild-type and mutant Rheb to vesicular structures in the cytoplasm, overlapping with the endoplasmic reticulum.
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1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. hjiang@scripps.edu
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D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D009479:Neuropeptides / Q000737:chemistry / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D054876:Prenylation; D011494:Protein Kinases / Q000502:physiology; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D051840:Y-Box-Binding Protein 1
D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006160:Guanosine Triphosphate; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D051840:Y-Box-Binding Protein 1; C085126:FOXO1 protein, human; C490211:RHEB protein, human; C070856:YBX1 protein, human; C546842:MTOR protein, human