Rheb activation of mTOR and S6K1 signaling.
More than 10 years ago, Rheb (Ras homolog enriched in brain) was identified as a highly conserved protein that is a member of the Ras superfamily of small GTPases, which play critical roles in cell growth and proliferation. Recently, a convergence of genetic and biochemical evidence from yeast, Drosophila, and mammalian cells has placed Rheb upstream of the mammalian target of rapamycin (mTOR) and immediately downstream of the tumor suppressors TSC1 (hamartin) and TSC2 (tuberin). Rheb plays a key role in the regulation of cell growth in response to growth factors, nutrients, and amino acids linking PI3K and TOR signaling. Rheb activation of the nutrient and energy-sensitive TOR pathway leads to the direct phosphorylation of two known downstream translational control targets by mTOR, the 40S ribosomal S6 kinase 1 (S6K1) and the eukaryotic translation initiation factor 4E (eIF4E)- binding protein 1 (4E-BP1). Appropriate regulation of this pathway is crucial for the proper control of cell growth, proliferation, survival, and differentiation. Inappropriate regulation of these signaling molecules, therefore, can lead to a variety of human diseases. In this chapter, we describe cell biological and biochemical methods commonly used to study Rheb activation and dissect its role in the mTOR-signaling pathway.
Hanrahan
Jessie
J
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Blenis
John
J
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D048429:Cell Size; D004330:Drosophila; D029721:Drosophila Proteins / Q000502:physiology*; D004789:Enzyme Activation; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D020690:GTPase-Activating Proteins / Q000032:analysis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014162:Transfection / Q000379:methods
D002352:Carrier Proteins; D029721:Drosophila Proteins; C499526:Eif4ebp1 protein, rat; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D010750:Phosphoproteins; D000076205:Ras Homolog Enriched in Brain Protein; C490212:Rheb protein, Drosophila; C490213:Rheb protein, mouse; D051231:Farnesyltranstransferase; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus