Rag GTPases - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 271

Chapter 12
Rag GTPases
Jenna L. Jewell and Kun-Liang Guan
Abstract The Rag GTPases appear to reside on the lysosome and link amino acid
stimulation to mTOR complex 1 (mTORC1) activation. mTORC1 couples nutrient
availability to cell growth. Dysregulation of mTORC1 is implicated in a number of
human diseases, including cancer and diabetes. In response to amino acid avail-
ability the Rag GTPases are regulated by the Ragulator and GATOR complexes,
which are a guanine nucleotide exchange factor (GEF) and GTPase activating
protein (GAP), respectively. Here we review the current knowledge of Rag
GTPases, with emphasis on amino acid-dependent regulation of mTORC1.
Keywords Rag GTPases ￿ mTORC1 ￿ amino acids ￿ Ragulator ￿ Gator ￿ v-ATPase
￿ lysosome
12.1 Discovery and Unique Properties of Rag GTPases
Rag GTPases have recently been identified as key components of the amino acid
signaling pathway to activate mTOR complex 1 (mTORC1). Rag GTPases belong
to the Ras superfamily; however, they have unique characteristics that distinguish
them from other small GTPases. For example, Rag GTPases have a long carboxyl-
terminal domain, lack a membrane-targeting sequence, and can form heterodimers
(Nakashima et al. 1999 ; Sekiguchi et al. 2001 ). There are four Rag proteins in
mammals: RagA and Rag B, which have high sequence similarity and are func-
tionally redundant; and RagC and RagD, which are also highly related in sequence
and are functionally equivalent. RagA or RagB forms a heterodimer with either
RagC or RagD, with the possibility of forming four distinct complex arrangements
(Sekiguchi et al. 2001 ). In Saccharomyces cerevisiae , the RagA/B orthologue Gtr1