Rag GTPases - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 281

GDP

GTP

Nprl2

WDR24

Seh1l

RagA/B DEPDC5

WDR59

Ragulator

Nprl3

Sec13 Mios

RagC/D

GTP

GATOR1 GATOR2

Lysosome

GDP

GTP

Np2

Sea2

Seh1

Iml1

Gtr1
Gtr2

Sea3

Ego1,3 Np3

Sec13 Sea4

GTP

SEACIT SEACAT

Vacuole

Fig. 12.2 Rag GTPase regulation by the multimeric GATOR complex. Under amino acid
starvation conditions the multimeric GATOR complex negatively regulates the Rag GTPases in
mammals and yeast. In mammals, the GATOR complex is comprised of two subcomplexes called
GATOR1 and GATOR2 ( top ). GATOR1 acts as a GAP for RagA/B exchanging GTP for GDP.
GATOR1 inactivates the Rag complex and thus mTORC1 activation. GATOR2 is thought to
inhibit the GATOR1 complex, although the mechanistic details are obscure. In yeast, SEACIT
(similar to GATOR1) acts as a GAP for Gtr1 (RagA/B orthologue) exchanging GTP for GDP,
inhibiting TORC1 ( bottom ). SEACAT (similar to GATOR2) negatively regulates SEACIT. How
amino acids specifically regulate these complexes is not known

12.3.5 Folliculin

Two recent studies identified folliculin (FLCN) as an important component
involved in amino acid signaling to mTORC1. A human disease referred to as
Birt-Hogg-Dub ´ syndrome arises from loss-of-function mutations in the FLCN
gene. Birt-Hogg-Dub ´ syndrome is characterized by fibrofolliculomas (benign hair
follicle tumors) and a strong predisposition towards the development of pneumo-
thorax, pulmonary cysts, and renal carcinomas (Birt et al. 1977 ; Nickerson
et al. 2002 ). Interestingly, FLCN is evolutionarily conserved, but its precise molec-
ular function is unknown (Schmidt 2013 ; van Slegtenhorst et al. 2007 ). Both studies
revealed FLCN to be critical for mTORC1 activation and lysosomal localization
(Petit et al. 2013 ; Tsun et al. 2013 ). Moreover, under amino acid starvation
conditions, FLCN was recruited to the lysosome where it directly interacted with
the Rag GTPases. A differing detail between the two studies is that one study found
that FLCN, promoted by FNIP1 (a folliculin binding protein), bound to the GTPase
domain of RagA (Petit et al. 2013 ), whereas the other study identified folliculin-
FNIP as a GAP for RagC/D (Tsun et al. 2013 ). There is evidence in yeast that FLCN
plays a role in the amino acid signaling cascade to TORC1. Deletion mutants for the
budding yeast orthologues of FLCN (LST7) and the Rags (Gtr1 and Gtr2) exhibited
similar growth sensitivities to various environmental and chemical insults, using a
chemical genomic screen (Hillenmeyer et al. 2008 ).