Transport to Rhebpress activity

Abstract

The small GTPases from the rat sarcoma (Ras) superfamily are a heterogeneous group of proteins of about 21 kDa that act as molecular switches, modulating cell signaling pathways and controlling diverse cellular processes. They are active when bound to guanosine triphosphate (GTP) and inactive when bound to guanosine diphosphate (GDP). Ras homolog enriched in brain (Rheb) is a member of the Ras GTPase superfamily and a key activator of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). We recently determined that microspherule protein 1 (MCRS1) maintains Rheb at lysosomal surfaces in an amino acid-dependent manner. MCRS1 depletion promotes the formation of the GDP-bound form of Rheb, which is then delocalized from the lysosomal platform and transported to endocytic recycling vesicles, leading to mTORC1 inactivation. During this delocalization process, Rheb-GDP remains farnesylated and associated with cellular endomembranes. These findings provide new insights into the regulation of small GTPases, whose activity depends on both their GTP/GDP switch state and their capacity to move between different cellular membrane-bound compartments. Dynamic spatial transport between compartments makes it possible to alter the proximity of small GTPases to their activatory sites depending on the prevailing physiological and cellular conditions.

Silencing of RHEB inhibits cell proliferation and promotes apoptosis in colorectal cancer cells via inhibition of the mTOR signaling pathway

“…Moreover, in lymphangioleiomyomatosis, the function loss of either the tuberous sclerosis complex 1 (TSC1) or TSC2 was confirmed to result in an increased activity of RHEB, thus promoting the progression of the disease (Makovski et al, ). Furthermore, RHEB is commonly known as a member of the Ras family, acting as the upstream activator of the mammalian target of rapamycin complex 1 (mTORC1; Garrido, Brandt, & Djouder, ). A previous study has demonstrated that RHEB‐mTORC1 might be the pivotal axis in regulating cell growth in cooperation with nutrient availability in the environment (Babcock & Quilliam, ).…”

Diet, Microbiota, and Colorectal Cancer

“…Moreover, AKT signals through the tuberous sclerosis complex TSC1/2, which acts as a GTPase-activating protein (GAP) for the Ras homologue enriched in brain (Rheb) GTPase (Fawal et al., 2015). mTORC1 is regulated and activated by Rheb in its GTP form; in the absence of GF, TSC2 inactivates Rheb by hydrolyzing GTP and keeping it in its inactive GDP-bound state (Garrido et al., 2016). Upon TSC1/2 inhibition, GTP-bound Rheb binds to and activates mTORC1 at the lysosomal surface.…”