Publication Date:
2011-06-11
Description:
The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177140/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177140/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hsu, Peggy P -- Kang, Seong A -- Rameseder, Jonathan -- Zhang, Yi -- Ottina, Kathleen A -- Lim, Daniel -- Peterson, Timothy R -- Choi, Yongmun -- Gray, Nathanael S -- Yaffe, Michael B -- Marto, Jarrod A -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- GM68762/GM/NIGMS NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA103866-09/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Jun 10;332(6035):1317-22. doi: 10.1126/science.1199498.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21659604" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line
;
GRB10 Adaptor Protein/*metabolism
;
Humans
;
Insulin/metabolism
;
Intercellular Signaling Peptides and Proteins/*metabolism
;
Mass Spectrometry
;
Mice
;
Multiprotein Complexes
;
Naphthyridines/pharmacology
;
Phosphoproteins/metabolism
;
Phosphorylation
;
Proteins/*metabolism
;
Proteome/metabolism
;
*Signal Transduction
;
Sirolimus/pharmacology
;
TOR Serine-Threonine Kinases/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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