User:Hannes Röst/Article2

Rheb (Ras homolog enriched in brain) is a small monomeric Ras-like GTPase conserved from yeast to mammals that stimulates the activity of (m)TOR and thereby impinges on cell growth and cell cycle control.

Regulation
Rheb is a GTPase, meaning that it can be found in two forms: an active GTP-bound form and an inactive GDP-bound form. The hydrolysis of GTP to GDP by Rheb is catalyzed by the heterodimeric GTPase activating proteins (GAPs) tuberous sclerosis 1 and 2 (TSC1/2). TSC1/2 are known tumor suppressors that directly target Rheb-GTP.

There are many factors, including nutrients, growth factors, stress, and energy status, that give regulatory input to Rheb and (m)TOR, though mostly in an indirect fashion. Insulin signaling, for example, leads to the inactivation of the GAP TSC1/2, thereby inhibiting the hydrolysis of the GTP bound to Rheb, leaving it in its active state. By this mechanism, insulin signaling activates mTOR.

Mechanism of Function
Rheb can activate mTOR only in its GTP bound form. Rheb-GTP activates mTOR by binding directly to FKBP38, a member of the FK506-binding protein family. FKBP38 is a mitochondrial protein that acts as an endogenous inhibitor of mTOR.

Therefore the binding of Rheb-GTP to FKBP38 sequesters the inhibitor of mTOR leading to mTOR signaling that, in turn, induces cell growth and proliferation.

Structure
Rheb shares sequence homology with other small GTPases, especially with the Ras/Rap-subfamily (30-40% sequence homology). The crystal structure of human Rheb (RHEB) was solved in the GDP-, GTP- and GppNHp- (GTP analog) bound forms.

RHEB is a 22 kD protein with 184 amino acids. The 169 residues form the GTPase domain, the 15 c-terminal residues are hypervariable with a CAAX-box important for farnesylation and membrane association. As in other small GTPases, switch I of RHEB adopts different conformational states in the GTP- and the GDP-bound form. Unlike most other small GTPases, the switch II of RHEB undergoes only minor conformational changes during the GTP/GDP cycling. Rheb has a very low intrinsic GTPase activity and a high basal GTP level. The protein is therefore supposed to be constitutively active. Nevertheless, it is an open question if an additional GEF (Guanosine Exchange Factor) exists as for other small GTPases.

The mechanism of Rheb inactivation is not clear yet, but due to the high sequence homology of TSC2’s C-terminus with the catalytic domain of Rap-Rap1GAP, a similar catalytic asparagine in both GAPs and its mutation in tuberous sclerosis patients, a mechanism for GTPase activation similar to the one of Rap-Rap1GAP has been suggested

The protein Bnip3 was recently found to mediate the hypoxia-induced inhibition of TORC1 signaling in at least two different ways. Hypoxia induces the expression and activation of Bnip3 which hereupon binds and inhibits Rheb. Although the molecular mechanisms of how Bnip3 inhibits Rheb remain elusive, the inhibition requires at least two different Binp3 activities: binding of Bnip3 to Rheb and a decrease in Rheb GTP levels.

Disease Relevance
There is not very much known about the role of Rheb in human diseases, but it is known that the GAP of Rheb, Tsc1/2, is a tumor suppressor. It has repeatedly been observed that Rheb is overexpressed in cancer cell lines. Also, in 2006, Patel et. al found that increased Rheb-TOR signaling enhances sensitivity of the whole organism to oxidative stress.

As for any member of a crucial pathway like the one centered around TOR, it can be expected that ongoing research will reveal a role for Rheb in many disease states in the future, especially in the context of growth control deficits.