TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity.
Target of rapamycin (TOR) plays a central role in cell growth regulation by integrating signals from growth factors, nutrients, and cellular energy levels. TOR forms two distinct physical and functional complexes, termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2). TORC1, which is sensitive to rapamycin, regulates translation and cell growth, whereas TORC2, which is insensitive to rapamycin, regulates cell morphology and cell growth. The Ras homology enriched in brain (Rheb) small GTPase is known to be a key upstream activator of TORC1, although the mechanism of Rheb in TORC1 activation remains to be determined. However, the function of Rheb in the TORC2 regulation has not been elucidated. By measuring Akt and S6K phosphorylation as a functional assay for TORC1 and -2, here, we report that dRheb has an inhibitory effect on dTORC2 activity in Drosophila S2 cells. This negative effect of dRheb on dTORC2 is possibly due to a feedback mechanism involving dTORC1 and dS6K. We also observed that Rheb does not activate TORC2 in human embryonic kidney 293 cells, although it potently stimulates TORC1. Furthermore, tuberous sclerosis complex 1 (TSC1) and TSC2, which are negative regulators of Rheb, have negative and positive effects on TORC1 and -2, respectively. Our observations suggest that TSC1/2 and Rheb have different effects on the activity of TORC1 and -2, further supporting the complexity of TOR regulation.
Yang
Qian
Q
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Inoki
Ken
K
Kim
Eunjung
E
Guan
Kun-Liang
KL
D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C500984:CRTC1 protein, human; C493245:CRTC2 protein, human; D029721:Drosophila Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D010750:Phosphoproteins; D000076205:Ras Homolog Enriched in Brain Protein; C490212:Rheb protein, Drosophila; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D020559:Monomeric GTP-Binding Proteins