Rag proteins are Ras-family GTP-binding proteins. Amino acid nutrient signaling is mediated by the Rag family (Kim & Guan 2009). Mammals express four Rag proteins (RRAGA-D) that form heterodimers. RRAGA (RagA) and RRAGB (RagB) can both form a heterodimer with one of RRAGC (RagC) or RRAGD (RagD), which are functionally redundant (Hirose et al. 1998, Sancak et al. 2008, Schurmann et al. 1995, Sekiguchi et al., 2001). Rag heterodimers containing GTP-bound RagB interact with mTORC1, and amino acids induce the mTORC1-Rag interaction by promoting the loading of RagB with GTP, which enables it to directly interact with the raptor component of mTORC1. RagB mutated to constitutively bind GTP immunoprecipitated raptor and mTOR more strongly than complexes containing wild-type RagB or RagB:GDP. The GDP-bound form of RagC increased the amount of copurifying mTORC1, so that a heterodimer complex of RagB:GTP and RagC:GDP recovered more mTORC1 than any other heterodimer (Sancak et al. 2008). It is not clear how Rag GTPases are regulated by the availability of amino acids (Jung et al. 2010, Betz & Hall 2013). Signalling may start at the cell membrane where specific SLC membrane transport proteins regulate amino acid levels and mTOR activity (Nicklin et al. 2009).
Thoreen, CC, Shaul, YD, Sabatini, DM, Sancak, Y, Bar-Peled, L, Lindquist, RA, Peterson, TR
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