The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

doi:10.1126/SCIENCE.1157535

Home
/
Papers
/
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

Journal Article•DOI•

The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

Yasemin Sancak¹, Timothy R. Peterson¹, Yoav D. Shaul¹, Robert A. Lindquist¹, Carson C. Thoreen¹, Liron Bar-Peled¹, David M. Sabatini¹, David M. Sabatini² - Show less +4 more•Institutions (2)

Massachusetts Institute of Technology¹, Broad Institute²

13 Jun 2008-Science (American Association for the Advancement of Science)-Vol. 320, Iss: 5882, pp 1496-1501

TL;DR: It is found that the Rag proteins—a family of four related small guanosine triphosphatases (GTPases)—interact with mTORC1 in an amino acid–sensitive manner and are necessary for the activation of the m TORC1 pathway by amino acids.

read less

Abstract: The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.

...read moreread less

Content maybe subject to copyright Report

Citations

PDF

Open Access

More filters

mTOR Signaling in Growth Control and Disease

[...]

Mathieu Laplante¹, David M. Sabatini¹•Institutions (1)

Massachusetts Institute of Technology¹

01 Apr 2012

TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.

...read moreread less

Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

...read moreread less

6,268 citations

Journal Article•DOI•

mTOR signaling in growth control and disease.

[...]

Mathieu Laplante¹, David M. Sabatini¹•Institutions (1)

Massachusetts Institute of Technology¹

13 Apr 2012-Cell

TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.

...read moreread less

5,792 citations

Cites background from "The Rag GTPases Bind Raptor and Med..."

...…evidence is needed to support this connection because the YY1 response element was not identified as a motif enriched in the promoters of mTORC1-regulated genes (Düvel et al., 2010) and little endogenous mTORC1 is found in the nucleus (Sancak et al., 2010; Sancak et al., 2008; Zoncu et al., 2011)....
[...]
...In 2008, two groups independently discovered that amino acid-dependent activation of mTORC1 requires the Rag GTPases (Kim et al., 2008; Sancak et al., 2008)....
[...]
...Through an unknown mechanism, amino acids promote the loading of RagA/B with GTP, which enables the heterodimer to interact with the raptor component of mTORC1 (Sancak et al., 2008)....
[...]
...The ATPase activity of the v-ATPase and the associated rotation of its V0 section appear to be essential to relay the amino acids signal from the lysosomal lumen to the Ragulator and Rag GTPases but exactly how the v-ATPase functions to do so is unknown....
[...]
...This interaction results in the translocation of mTORC1 from a poorly characterized cytoplasmic location to the lysosomal surface, where the Rag GTPases dock on a multisubunit complex called Ragulator (Sancak et al., 2010)....
[...]

Journal Article•DOI•

mTOR Signaling in Growth, Metabolism, and Disease.

[...]

Robert A. Saxton, David M. Sabatini

09 Mar 2017-Cell

TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR signaling network contributes to human disease is highlighted.

...read moreread less

4,719 citations

Cites background from "The Rag GTPases Bind Raptor and Med..."

...A breakthrough in the understanding of amino acid sensing by mTORC1 came with the discovery of the heterodimeric Rag GTPases as components of the mTORC1 pathway (Kim et al., 2008; Sancak et al., 2008)....
[...]

Journal Article•DOI•

mTOR: from growth signal integration to cancer, diabetes and ageing

[...]

Roberto Zoncu¹, Alejo Efeyan¹, David M. Sabatini¹•Institutions (1)

Massachusetts Institute of Technology¹

01 Jan 2011-Nature Reviews Molecular Cell Biology

TL;DR: Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.

...read moreread less

Abstract: In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.

...read moreread less

3,641 citations

Journal Article•DOI•

Regulation Mechanisms and Signaling Pathways of Autophagy

[...]

Congcong He¹, Daniel J. Klionsky¹•Institutions (1)

University of Michigan¹

17 Nov 2009-Annual Review of Genetics

TL;DR: The current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagic for cell survival and homeostasis are presented.

...read moreread less

Abstract: Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Defective autophagy plays a significant role in human pathologies, including cancer, neurodegeneration, and infectious diseases. We present our current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagy for cell survival and homeostasis. We also review the recent advances on the molecular mechanisms that regulate the autophagy machinery at various levels, from transcriptional activation to post-translational protein modification.

...read moreread less

3,249 citations

1
2
3
4
…
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200

Collapse

References

PDF

Open Access

More filters

Journal Article•DOI•

mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery

[...]

Do Hyung Kim¹, Dos D. Sarbassov¹, Siraj M. Ali¹, Jessie E. King¹, Robert R. Latek¹, Hediye Erdjument-Bromage², Paul Tempst², David M. Sabatini¹ - Show less +4 more•Institutions (2)

Massachusetts Institute of Technology¹, Memorial Sloan Kettering Cancer Center²

26 Jul 2002-Cell

TL;DR: It is reported that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway that through its association with mTOR regulates cell size in response to nutrient levels.

...read moreread less

2,902 citations

Journal Article•DOI•

Defining the Role of mTOR in Cancer

[...]

David A. Guertin¹, David A. Guertin², David M. Sabatini², David M. Sabatini¹•Institutions (2)

Massachusetts Institute of Technology¹, Broad Institute²

10 Jul 2007-Cancer Cell

TL;DR: Recent progress in understanding mTOR signaling is discussed, paying particular attention to its relevance in cancer and the use of rapamycin in oncology.

...read moreread less

2,732 citations

Journal Article•DOI•

Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control

[...]

Robbie Loewith¹, Estela Jacinto¹, Stephan Wullschleger¹, Anja Lorberg¹, José L. Crespo¹, Debora Bonenfant¹, Wolfgang Oppliger¹, Paul Jenoe¹, Michael N. Hall¹ - Show less +5 more•Institutions (1)

University of Basel¹

01 Sep 2002-Molecular Cell

TL;DR: Two functionally distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling.

...read moreread less

1,769 citations

Journal Article•DOI•

Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action.

[...]

Kenta Hara¹, Yoshiko Maruki¹, Xiaomeng Long², Ken-ichi Yoshino¹, Noriko Oshiro¹, Sujuti Hidayat¹, Chiharu Tokunaga¹, Joseph Avruch², Kazuyoshi Yonezawa¹ - Show less +5 more•Institutions (2)

Kobe University¹, Harvard University²

26 Jul 2002-Cell

TL;DR: Raptor is an essential scaffold for the mTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo and yields an array of phenotypes that closely resemble those produced by inactivation of Ce-TOR.

...read moreread less

1,752 citations

Journal Article•DOI•

Growing roles for the mTOR pathway

[...]

Dos D. Sarbassov¹, Siraj M. Ali¹, David M. Sabatini¹•Institutions (1)

Massachusetts Institute of Technology¹

01 Dec 2005-Current Opinion in Cell Biology

TL;DR: Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.

...read moreread less

1,543 citations