Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin.
The Ras-homologous GTPase Rheb that is conserved from yeast to human appears to be involved not only in cell growth but also in nutrient uptake. Recent biochemical analysis revealed that tuberous sclerosis complex (TSC), a GTPase-activating protein (GAP), deactivates Rheb and that phosphatidylinositol 3'-kinase (PI3k)-Akt/PKB kinase pathway activates Rheb through inhibition of the GAP-mediated deactivation. Although mammalian target of rapamycin (mTOR) kinase is implicated in the downstream target of Rheb, the direct effector(s) and exact functions of Rheb have not been fully elucidated. Here we identified that Rheb expression in cultured cells induces the formation of large cytoplasmic vacuoles, which are characterized as late endocytic (late endosome- and lysosome-like) components. The vacuole formation required the GTP form of Rheb, but not the activation of the downstream mTOR kinase. These results suggest that Rheb regulates endocytic trafficking pathway independent of the previously identified mTOR pathway. The physiological roles of the two Rheb-dependent signaling pathways are discussed in terms of nutrient uptake and cell growth or cell cycle progression.
Saito
Kota
K
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Araki
Yasuhiro
Y
Kontani
Kenji
K
Nishina
Hiroshi
H
Katada
Toshiaki
T
D000818:Animals; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D004285:Dogs; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014018:Tissue Distribution; D014617:Vacuoles / Q000378:metabolism
D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; C490211:RHEB protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human