RhebGDP

RhebGDP is the GDP-bound, inactive form of Rheb, a small GTPase of the Ras superfamily. Rheb cycles between a GTP-bound active state (Rheb-GTP) and a GDP-bound inactive state (Rheb-GDP), with the interconversion principally governed by the tuberous sclerosis complex (TSC1/TSC2). TSC2 acts as a GTPase-activating protein, promoting hydrolysis of Rheb-GTP to Rheb-GDP and thereby reducing downstream signaling.

Localization and function are tied to the nucleotide state. Rheb is farnesylated at its C-terminus, which helps anchor it to membranes such as lysosomes where mTORC1 resides. Rheb-GTP directly activates mTORC1, promoting anabolic processes. Rheb-GDP, in contrast, has a reduced affinity for mTORC1 and cannot stimulate its kinase activity effectively.

Regulation integrates growth factors, energy, and nutrients. Growth factors activate PI3K-AKT signaling, which inhibits TSC2, allowing accumulation of Rheb-GTP and activation of mTORC1. In contrast, energy or nutrient stress activates AMPK, which stimulates TSC2, increasing Rheb-GDP levels and suppressing mTORC1 signaling.

Clinical and biological relevance are linked to mTORC1 output. Dysregulation of TSC1/TSC2 or Rheb activity can lead to aberrant mTORC1 signaling, contributing to diseases such as tuberous sclerosis complex and related tumorigenesis in certain contexts.

Notes on exchange: The exact guanine-nucleotide exchange mechanism for Rheb is not fully characterized, and there is no widely accepted dedicated Rheb GEF. Exchange between GDP and GTP is relatively slow and depends on GAP-mediated hydrolysis and cellular context.