Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-10-16

AUTHORS

J Avruch, K Hara, Y Lin, M Liu, X Long, S Ortiz-Vega, K Yonezawa

ABSTRACT

Target of Rapamycin (TOR), a giant protein kinase expressed by all eucaryotic cells, controls cell size in response to nutrient signals. In metazoans, cell and organismal growth is controlled by nutrients and the insulin/insulin-like growth factor (IGF) system, and the understanding of how these inputs coordinately regulate TOR signaling has advanced greatly in the past 5 years. In single-cell eucaryotes and Caenorhabditis elegans, TOR is a dominant regulator of overall mRNA translation, whereas in higher metazoans, TOR controls the expression of a smaller fraction of mRNAs that is especially important to cell growth. TOR signals through two physically distinct multiprotein complexes, and the control of cell growth is mediated primarily by TOR complex 1 (TORC1), which contains the polypeptides raptor and LST8. Raptor is the substrate binding element of TORC1, and the ability of raptor to properly present substrates, such as the translational regulators 4E-BP and p70 S6 kinase, to the TOR catalytic domain is essential for their TOR-catalysed phosphorylation, and is inhibited by the Rapamycin/FKBP-12 complex. The dominant proximal regulator of TORC1 signaling and kinase activity is the ras-like small GTPase Rheb. Rheb binds directly to the mTOR catalytic domain, and Rheb-GTP enables TORC1 to attain an active configuration. Insulin/IGF enhances Rheb GTP charging through the ability of activated Akt to inhibit the Rheb-GTPase-activating function of the tuberous sclerosis heterodimer (TSC1/TSC2). Conversely, energy depletion reduces Rheb-GTP charging through the ability of the adenosine monophosphate-activated protein kinase to phosphorylate TSC2 and stimulate its Rheb-GTPase activating function, as well as by HIFα-mediated transcriptional responses that act upstream of the TSC1/2 complex. Amino-acid depletion inhibits TORC1 acting predominantly downstream of the TSC complex, by interfering with the ability of Rheb to bind to mTOR. The components of the insulin/IGF pathway to TORC1 are now well established, whereas the elements mediating the more ancient and functionally dominant input of amino acids remain largely unknown. More... »

PAGES

6361-6372

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1209882

DOI

http://dx.doi.org/10.1038/sj.onc.1209882

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1015419210

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17041622


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79 elegans
80 elements
81 energy depletion
82 eucaryotes
83 eucaryotic cells
84 expression
85 factor system
86 fraction
87 function
88 giant protein kinases
89 growth
90 growth factor system
91 heterodimers
92 higher metazoans
93 input
94 insulin
95 insulin-like growth factor (IGF) system
96 insulin/IGF
97 insulin/IGF pathway
98 insulin/insulin-like growth factor (IGF) system
99 kinase
100 mRNA
101 mRNA translation
102 mTOR
103 mTOR catalytic domain
104 metazoans
105 monophosphate
106 multiprotein complexes
107 nutrient signals
108 nutrients
109 organismal growth
110 overall mRNA translation
111 p70 S6 kinase
112 pathway
113 phosphorylation
114 present substrate
115 protein kinase
116 proximal regulator
117 rapamycin
118 raptors
119 regulation
120 regulator
121 response
122 signals
123 size
124 small GTPase Rheb
125 small fraction
126 substrate
127 system
128 target
129 target of rapamycin
130 transcriptional response
131 translation
132 understanding
133 years
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