RhebGTPasen

RhebGTPasen, commonly referred to as RHEB, is a small GTPase of the Ras superfamily that plays a central role in cell growth signaling. In humans there are two related genes: RHEB (often called RHEB1) and RHEBL1 (also known as RHEB2). The encoded proteins cycle between an active GTP-bound state and an inactive GDP-bound state, regulating downstream pathways in response to extracellular and intracellular cues.

The primary function of RHEB is to regulate mTORC1, the mammalian target of rapamycin complex 1, a key kinase complex that promotes protein synthesis, lipid metabolism, and cell growth. When bound to GTP, RHEB directly activates mTORC1, leading to phosphorylation of downstream targets such as S6K1 and 4E-BP1. Activation of mTORC1 by RHEB is typically coupled to lysosomal localization and is influenced by amino acid sensing via Rag GTPases, which recruit mTORC1 to the lysosome, while RHEB-GTP provides a necessary activation signal.

Regulation of RHEB involves tight control of its GTP/GDP cycle. The tuberous sclerosis complex, consisting of TSC1 and TSC2, acts as a GTPase-activating protein for RHEB, converting RHEB-GTP to RHEB-GDP and thereby inhibiting mTORC1. Growth factor signaling through AKT inhibits TSC2, allowing RHEB to remain GTP-bound and activate mTORC1; energy stress can activate AMPK, which promotes TSC2 activity and mTORC1 inhibition.

Dysregulation of RHEB–mTORC1 signaling is associated with conditions such as tuberous sclerosis complex, cancer, and metabolic disorders. RHEB therefore serves as a crucial node linking nutrient and growth signals to cellular growth decisions.