Ser636
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Home > Phosphorylation Site Page: > Ser636  -  IRS1 (human)

Site Information
sGDyMPMsPKsVSAP   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447506

In vivo Characterization
Methods used to characterize site in vivo:
immunoprecipitation ( 12 , 23 , 34 ) , mass spectrometry ( 2 , 5 , 6 , 7 , 8 , 10 , 12 , 13 , 14 , 15 , 18 , 24 , 27 ) , mutation of modification site ( 23 , 26 ) , phospho-antibody ( 3 , 4 , 16 , 17 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 28 , 29 , 30 , 31 , 33 , 34 ) , western blotting ( 3 , 4 , 16 , 17 , 19 , 20 , 21 , 22 , 23 , 25 , 26 , 30 , 31 , 34 )
Disease tissue studied:
breast cancer ( 5 , 6 , 10 , 17 , 21 ) , breast ductal carcinoma ( 5 ) , HER2 positive breast cancer ( 2 ) , luminal A breast cancer ( 2 ) , luminal B breast cancer ( 2 ) , breast cancer, surrounding tissue ( 2 ) , breast cancer, triple negative ( 2 , 5 ) , liver cancer ( 20 , 30 ) , lung cancer ( 10 ) , non-small cell lung cancer ( 10 ) , ovarian cancer ( 5 ) , pancreatic cancer ( 3 ) , pancreatic ductal adenocarcinoma ( 7 ) , diabetes mellitus ( 21 ) , type 2 diabetes ( 12 , 21 )
Relevant cell line - cell type - tissue:
'granulosa, luteal' ( 16 ) , 'muscle, skeletal' ( 12 , 24 , 29 , 30 , 34 ) , 'pancreatic, ductal'-pancreas ( 7 ) , 1321N1 (glial) ( 33 ) , 293 (epithelial) [AT1 (human), transfection, AT1R stable transfected HEK293] ( 15 ) , 293 (epithelial) ( 19 , 20 , 26 , 27 ) , 3T3 (fibroblast) [SHP-2 (mouse), homozygous knockout] ( 28 ) , 3T3 (fibroblast) ( 20 ) , 3T3-L1 (fibroblast) ( 20 , 25 ) , A549 (pulmonary) ( 8 ) , adipocyte-adipose tissue ( 31 ) , astrocyte ( 4 ) , breast ( 2 , 5 ) , BT-549 (breast cell) ( 10 ) , CHO-IR (fibroblast) [IRS1 (human), transfection] ( 23 ) , CHO-IR (fibroblast) ( 14 ) , H2009 (pulmonary) ( 10 ) , H2077 (pulmonary) ( 10 ) , H2887 (pulmonary) ( 10 ) , H322M (pulmonary) ( 10 ) , H4IIe (hepatic) ( 20 ) , HCC1359 (pulmonary) ( 10 ) , HCC1937 (breast cell) ( 10 ) , HCC2279 (pulmonary) ( 10 ) , HCC366 (pulmonary) ( 10 ) , HCC4006 (pulmonary) ( 10 ) , HCC78 (pulmonary) ( 10 ) , HCC827 (pulmonary) ( 10 ) , HEK293T (epithelial) ( 26 ) , HeLa (cervical) ( 13 , 18 ) , HepG2 (hepatic) ( 30 ) , HMLER ('stem, breast cancer') [CXCR4 (human), knockdown] ( 6 ) , HMLER ('stem, breast cancer') ( 6 ) , HOP62 (pulmonary) ( 10 ) , L6 (myoblast) ( 29 ) , LCLC-103H (pulmonary) ( 10 ) , liver ( 21 , 30 ) , LOU-NH91 (squamous) ( 10 ) , MCF-7 (breast cell) ( 10 ) , MDA-MB-231 (breast cell) ( 10 , 17 ) , MDA-MB-453 (breast cell) ( 21 ) , MEF (fibroblast) ( 26 ) , NCI-H1395 (pulmonary) ( 10 ) , NCI-H1568 (pulmonary) ( 10 ) , NCI-H157 (pulmonary) ( 10 ) , NCI-H1666 (pulmonary) ( 10 ) , NCI-H2030 (pulmonary) ( 10 ) , NCI-H2172 (pulmonary) ( 10 ) , NCI-H322 (pulmonary) ( 10 ) , NCI-H460 (pulmonary) ( 10 ) , NCI-H520 (squamous) ( 10 ) , NCI-H647 (pulmonary) ( 10 ) , ovary ( 5 ) , PC-1 (pancreatic) ( 3 ) , PC1.0 (pancreatic) ( 3 ) , PC9 (pulmonary) ( 10 ) , vascular smooth muscle cell ('muscle, smooth') ( 22 )

Upstream Regulation
Regulatory protein:
Akt1 (human) ( 19 ) , Akt2 (human) ( 19 ) , LST8 (human) ( 19 ) , mTOR (human) ( 19 , 26 ) , p70S6K (human) ( 19 , 26 , 32 ) , P70S6KB (human) ( 26 ) , PDK1 (human) ( 19 ) , PIK3CA (human) ( 19 ) , Raptor (human) ( 19 ) , RHEB (human) ( 26 ) , RICTOR (human) ( 19 ) , Sin1 (human) ( 19 ) , TSC1 (human) ( 21 ) , TSC1 (mouse) ( 26 ) , TSC2 (mouse) ( 26 )
Putative in vivo kinases:
p70S6K (mouse) ( 20 , 26 )
Kinases, in vitro:
ERK2 (human) ( 23 ) , p70S6K (human) ( 20 )
Treatments:
4-HT ( 17 ) , 9cRA ( 17 ) , Akt_inhibitor_VIII ( 19 ) , amino_acids ( 29 ) , anisomycin ( 28 ) , carbachol ( 33 ) , dexamethasone ( 17 ) , dinoprost ( 16 ) , EGF ( 18 ) , insulin ( 12 , 14 , 19 , 24 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ) , ischemia ( 5 ) , LY294002 ( 19 ) , okadaic_acid ( 33 ) , PD98059 ( 34 ) , PDGF ( 33 ) , rapamycin ( 16 , 19 , 22 , 26 , 28 , 29 , 30 , 31 ) , retinoic_acid ( 17 ) , SB202190 ( 18 ) , serum ( 19 ) , siRNA ( 32 ) , SP600125 ( 28 ) , tamoxifen ( 17 ) , TNF ( 21 ) , U0126 ( 16 , 18 ) , wortmannin ( 19 )

Downstream Regulation
Effects of modification on IRS1:
intracellular localization ( 26 )
Effects of modification on biological processes:
carcinogenesis, induced ( 3 ) , cell motility, induced ( 3 )

Disease / Diagnostics Relevance
Relevant diseases:
pancreatic ductal adenocarcinoma ( 3 ) , type 2 diabetes ( 34 )

References 

1

Koh A, et al. (2018) Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell 175, 947-961.e17
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2

Mertins P, et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534, 55-62
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3

Tan X, et al. (2016) Phosphoproteome Analysis of Invasion and Metastasis-Related Factors in Pancreatic Cancer Cells. PLoS One 11, e0152280
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4

Garwood CJ, et al. (2015) Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Mol Brain 8, 51
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5

Mertins P, et al. (2014) Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics 13, 1690-704
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6

Yi T, et al. (2014) Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. Proc Natl Acad Sci U S A 111, E2182-90
24782546   Curated Info

7

Britton D, et al. (2014) Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets. PLoS One 9, e90948
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8

Kim JY, et al. (2013) Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells. Proc Natl Acad Sci U S A 110, 12414-9
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9

Shiromizu T, et al. (2013) Identification of missing proteins in the neXtProt database and unregistered phosphopeptides in the PhosphoSitePlus database as part of the Chromosome-centric Human Proteome Project. J Proteome Res 12, 2414-21
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10

Klammer M, et al. (2012) Phosphosignature predicts dasatinib response in non-small cell lung cancer. Mol Cell Proteomics 11, 651-68
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11

Beli P, et al. (2012) Proteomic Investigations Reveal a Role for RNA Processing Factor THRAP3 in the DNA Damage Response. Mol Cell 46, 212-25
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12

Langlais P, et al. (2011) Global IRS-1 phosphorylation analysis in insulin resistance. Diabetologia 54, 2878-89
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13

Kettenbach AN, et al. (2011) Quantitative phosphoproteomics identifies substrates and functional modules of aurora and polo-like kinase activities in mitotic cells. Sci Signal 4, rs5
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14

Langlais P, Mandarino LJ, Yi Z (2010) Label-free relative quantification of co-eluting isobaric phosphopeptides of insulin receptor substrate-1 by HPLC-ESI-MS/MS. J Am Soc Mass Spectrom 21, 1490-9
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15

Christensen GL, et al. (2010) Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists. Mol Cell Proteomics 9, 1540-53
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16

Arvisais E, et al. (2010) Prostaglandin F2alpha represses IGF-I-stimulated IRS1/phosphatidylinositol-3-kinase/AKT signaling in the corpus luteum: role of ERK and P70 ribosomal S6 kinase. Mol Endocrinol 24, 632-43
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17

Eto I (2010) Upstream molecular signaling pathways of p27(Kip1) expression: Effects of 4-hydroxytamoxifen, dexamethasone, and retinoic acids. Cancer Cell Int 10, 3
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18

Pan C, Olsen JV, Daub H, Mann M (2009) Global effects of kinase inhibitors on signaling networks revealed by quantitative phosphoproteomics. Mol Cell Proteomics 8, 2796-808
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19

Tzatsos A (2009) Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of insulin receptor substrate-1 (IRS-1) and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR. J Biol Chem 284, 22525-34
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20

Zhang J, et al. (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem 283, 35375-82
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21

Lee DF, et al. (2008) IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance. Int J Mol Med 22, 633-8
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22

Martin KA, et al. (2007) Rapamycin promotes vascular smooth muscle cell differentiation through insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt2 feedback signaling. J Biol Chem 282, 36112-20
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23

Luo M, et al. (2007) Phosphorylation of human insulin receptor substrate-1 at Serine 629 plays a positive role in insulin signaling. Endocrinology 148, 4895-905
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24

Yi Z, et al. (2007) Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle. Diabetes 56, 1508-16
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25

Vander Haar E, et al. (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9, 316-23
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26

Shah OJ, Hunter T (2006) Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Mol Cell Biol 26, 6425-34
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27

Luo M, et al. (2005) Identification of insulin receptor substrate 1 serine/threonine phosphorylation sites using mass spectrometry analysis: regulatory role of serine 1223. Endocrinology 146, 4410-6
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28

Hiratani K, et al. (2005) Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1. Biochem Biophys Res Commun 335, 836-42
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29

Tremblay F, et al. (2005) Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54, 2674-84
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30

Khamzina L, Veilleux A, Bergeron S, Marette A (2005) Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 146, 1473-81
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31

Tremblay F, et al. (2005) Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes. Endocrinology 146, 1328-37
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32

Um SH, et al. (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200-5
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33

Batty IH, Fleming IN, Downes CP (2004) Muscarinic-receptor-mediated inhibition of insulin-like growth factor-1 receptor-stimulated phosphoinositide 3-kinase signalling in 1321N1 astrocytoma cells. Biochem J 379, 641-51
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34

Bouzakri K, et al. (2003) Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52, 1319-25
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