Rheb

Rheb, short for Ras homolog enriched in brain, is a small GTPase of the Ras superfamily that participates in nutrient- and growth-factor–responsive signaling to promote cell growth. In mammals, there are two closely related Rheb family members: RHEB (often called Rheb1) and RHEBL1 (RhebL1). The proteins are roughly 180–200 amino acids in length and localize to membranes, including lysosome-associated compartments, where they participate in mTORC1 regulation.

Rheb functions as a molecular switch, cycling between an active GTP-bound state and an inactive GDP-bound state. The GTP-bound Rheb directly activates the mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of cell growth, protein synthesis, and metabolism. Activation of mTORC1 by Rheb requires proper lysosomal localization and signaling inputs such as amino acids, which are coordinated through Rag GTPases.

Rheb activity is tightly controlled by upstream signaling. The tuberous sclerosis complex (TSC1/TSC2) heterodimer acts as a GTPase-activating protein toward Rheb, converting Rheb-GTP to Rheb-GDP and inhibiting mTORC1. Growth-factor signaling through the PI3K–AKT pathway inhibits TSC1/TSC2, promoting Rheb-GTP accumulation and mTORC1 activation. Localization to membranes, particularly lysosomes, is important for effective mTORC1 stimulation.

Clinical and biological relevance: dysregulation of Rheb and the mTOR pathway is implicated in tuberous sclerosis complex–related tumors, cancer, metabolic disorders, and neurodevelopmental conditions. Pharmacological modulation of mTOR signaling, including rapamycin and related inhibitors, can affect cells with altered Rheb activity.

Paralogs and diversity: Rheb has related proteins such as RhebL1, and both participate in mTOR signaling with overlapping but distinct tissue expression and functional contributions.