SnapShot: mTORC1 Signaling at the Lysosomal Surface

1390

Cell 151, December 7, 2012 ©2012 Elsevier Inc.

DOI http://dx.doi.org/10.1016/j.cell.2012.11.038

A

B

A

B

D C d F c c c

A

G

E

v-ATPase

Gln

Gln

Leu

SLC7A5

Leu

GTP

p14 p18

HBXIP C7orf59

Ragulator complex

MP1

mTORC1 (active)

RagAGDP

RagAGTP

mTORC1 (inactive)

Rheb

GTP

Sestrin

p53

DNA damage

LY S O S O M E

Growth

GAP activity

CYTOPLASM

Movement away from the lysosomal surface

Redd1

O2 levels

pras40

mTORC1

mTOR

raptor

AMPK

mLST8

TBC1D7

Frizzled

TSC complex

TSC2

GSK3

Dsh1

Wnt

Wnt signaling

TSC1

LKB1

Energy levels ATP/AMP

TSC complex

CO M PLE X ES AT TH E LY SOSOM AL SU R FAC E

Ragulator RagA GDP RagC

GEF activity

FKBP12

Rapamycin

Movement to the lysosomal surface

SLC1A5

Gln

Lysosomal v-ATPase

H

B

E

G

a

Amino acids

?

Amino acid transporter

Amino acids

Nutrient signaling

Liron Bar-Peled and David M. Sabatini Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

SnapShot: mTORC1 Signaling at the Lysosomal Surface

GAP activity

1

PIP

2

NF1

PI3K

Rsk1

IRS

Tyrosine kinase receptor

Oncogene

Akt1

PDK1

PIP3

Pten

mTORC1 substrate

IKK`

TNF receptor

TNFD

TNF signaling

ULK1

ATG13

Autophagy

Lipid biosynthesis

Lysosome biogenesis

Energy metabolism

Protein synthesis

SREBP1/2

Lipin-1

TFEB

HIF1_

4EBP1

S6K1

DOWNS T REAM CELLULAR PROG RAM S REG ULAT ED B Y mT ORC1 ACTIVITY

Tumor suppressor

Erk1/2

Mek

Raf

Ras

GTP

GEF activity

SOS

GRB2

IGF

Growth factor signaling

FIP200

deptor

See online version for legend and references.

SnapShot: mTORC1 Signaling at the Lysosomal Surface Liron Bar-Peled and David M. Sabatini Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA In mammals, the mTOR complex 1 (mTORC1) ser/thr kinase regulates cellular and organismal growth in response to a variety of environmental and intracellular stimuli. Amino acid levels mediate the first step in the bipartite activation of mTORC1 by promoting its translocation from a cytosolic compartment to the lysosomal surface. By a poorly understood mechanism, amino acid sensing initiates from within the lysomal lumen and, in a process requiring the v-ATPase, activates the GEF activity of the Ragulator complex toward RagA within the heterodimeric Rag GTPases. Upon GTP binding, RagA recruits mTORC1 to the lysosomal surface, allowing it to interact with the small GTPase Rheb, a potent stimulator of mTORC1 kinase activity. Regulation of nucleotide binding state of Rheb by the tumor suppressor TSC, which is found at the lysosomal surface, is the second step in the activation of mTORC1. Many of the environmental and intracellular cues that impinge on mTORC1 funnel through TSC and regulate its GAP activity toward Rheb. Among them, growth factor signaling through the PI3K or Ras pathways leads to the activation of the protein kinases Akt and Rsk1, respectively, which phosphorylate and inhibit TSC function. The AMPK pathway becomes activated upon low energy levels and in a p53-dependent manner by DNA damage, leading to phosphorylation and activation of TSC and phosphorylation and inactivation of mTORC1. Reduction in oxygen levels induces Redd1 expression, which by an ill-defined process maintains TSC function. Once activated, mTORC1 enables growth by promoting anabolic programs while repressing catabolic processes. mTORC1 phosphorylates key effectors such as z1 and 4EBP1 to activate translation and inhibits autophagy by phosphorylating and inactivating ATG13 and ULK1. As a master regulator of cell metabolism, deregulation of the mTORC1 pathway is common in many human diseases. Cancers with aberrant mTORC1 activity, such as tuberous sclerosis and advanced renal cell carcinoma, are increasingly treated with analogs of the mTORC1 inhibitor Rapamycin. Furthermore, overactivation of this pathway leads to the downregulation of IRS1 and progression of type 2 diabetes. Although the mTORC1 pathway is absolutely required for mammalian development, reduction of mTORC1 activity in mice models through pharmacological inhibition not only enhances adult stem cell numbers, function, or both, but also extends murine life span. Abbreviations mTOR, mechanistic target of rapamycin; raptor, regulatory associated protein of mTOR; mLST8, mammalian lethal with SEC13 protein 8; pras40, proline-rich Akt substrate 40 kDa; Rheb, ras homolog enriched in brain; TSC, tuberous sclerosis complex; Rag, ras-related GTP binding; MP1, MAPK scaffold protein 1; HBXIP, hepatitis B virus X-interacting protein; v-ATPase, vacuolar H+-adenosine triphosphatase ATPase; GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein; ULK1, unc-51-like kinase 1; ATG13, autophagy-related protein 13; FIP200, FAK family kinase-interacting protein of 200 kDA; S6K1, p70 ribosomal S6 kinase 1; 4EBP1, 4E-binding protein 1; Redd, protein regulated in development and DNA damage response 1; TFEB, transcription factor EB; HIF1a, hypoxia-inducible factor 1a; LKB1, serine/threonine-protein kinase STK11; SREBP1, sterol regulatory element binding protein-1; AMPK, 5´-AMP-activated protein kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; PI3K, phosphatidylinositol 3-kinase; GRB2, growth factor receptor-bound protein 2; SOS, son-of-sevenless; NF1, neurofibromin 1; PDK1, phosphoinositide dependent kinase 1; IRS1, insulin receptor substrate 1; IGF, insulin-like growth factor; TNFa, tumor necrosis factor a; IKKB, inhibitor of nuclear factor k-B kinase subunit b; WNT, wingless; Dsh1, dishevelled 1; GSK3, glycogen synthase kinase 3; TK, tyrosine kinase; SLC1A5, solute carrier family 1 member 5; SLC7A5, solute carrier family 7 member 5; FKBP12, FK506-binding protein 12 KDa. 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1390.e1  Cell 151, December 7, 2012 ©2012 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cell.2012.11.038