Ras-related GTP-binding protein (Rag GTPase) (Rag GTPase)

Rag GTPases are a family of small GTP-binding proteins, including RagA, RagB, RagC, and RagD, that serve as critical nutrient sensors in eukaryotic cells [UniProt]. They function as obligate heterodimers, typically consisting of RagA or RagB paired with RagC or RagD, localized to the lysosomal membrane [PMID: 18497260]. In the presence of amino acids, the Rag complex adopts an active state (RagA/B-GTP and RagC/D-GDP) that recruits the mechanistic target of rapamycin complex 1 (mTORC1) to the lysosome, where it can be activated by Rheb [PMID: 18589070]. This recruitment is a fundamental step in coupling nutrient availability to cell growth, protein synthesis, and autophagy [PubMed]. Mutations in the Rag GTPase genes, particularly RRAGC, have been identified as drivers in follicular lymphoma, where they lead to constitutive mTORC1 activation independent of nutrient levels [PMID: 28114296]. While direct pharmacological inhibitors of Rag GTPases are currently in the preclinical stage, they represent a promising strategy for treating cancers and metabolic diseases characterized by aberrant mTORC1 signaling [Nature Reviews Drug Discovery]. Targeting the Rag-mTORC1 interaction may offer greater specificity and fewer side effects compared to traditional mTOR inhibitors like rapamycin [PMID: 25457612].

Other names

RRAGRagARagBRagCRagDRas-related GTP-binding protein ARas-related GTP-binding protein BRas-related GTP-binding protein CRas-related GTP-binding protein D

Inhibition of mTORC1 recruitment to the lysosomal surface by preventing the formation of the active Rag GTPase heterodimer complex [PMID: 18497260]. This can be achieved through competitive inhibition of GTP binding or stabilization of the inactive GDP-bound state of RagA/B [PMID: 25457612].