RHEBGTP

RhebGTP refers to the active, GTP-bound form of Rheb (Ras homolog enriched in brain), a small GTPase of the Ras superfamily that localizes to lysosomal membranes and acts as a central regulator of mTOR complex 1 (mTORC1) signaling. In its GTP-bound state, Rheb directly stimulates mTORC1 kinase activity, promoting protein synthesis, lipid biosynthesis, and cell growth in response to growth factors and nutrients. The GDP-bound form of Rheb is inactive in terms of mTORC1 activation.

Regulation of Rheb activity is controlled mainly by the tuberous sclerosis complex, TSC1/TSC2, which functions as a GTPase-activating protein (GAP) for Rheb, accelerating hydrolysis of GTP to GDP and thereby inhibiting mTORC1. Growth factor signaling through the PI3K/AKT pathway can inhibit TSC2, allowing accumulation of Rheb-GTP and activation of mTORC1. Nutrient status influences mTORC1 via Rag GTPases that recruit the complex to the lysosome, where Rheb-GTP can stimulate its activity. Thus, Rheb-GTP acts downstream of growth factors and energy/nutrient cues to modulate anabolic processes.

Localization and post-translational modification contribute to Rheb function. Rheb is a membrane-associated GTPase that is typically farnesylated at its C-terminus, helping anchor it to lysosomal membranes where mTORC1 resides. It cycles between GTP- and GDP-bound states through intrinsic GTPase activity, with nucleotide state and subcellular localization determining its ability to activate mTORC1.

Dysregulation of Rheb-GTP–driven signaling is implicated in cancer and tuberous sclerosis–related disorders. Pharmacological inhibition of mTORC1, such as with rapamycin, counteracts signaling driven by Rheb-GTP.