Ser307
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Home > Phosphorylation Site Page: > Ser307  -  IRS1 (human)

Site Information
TRRsRtEsItAtsPA   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 450190

In vivo Characterization
Methods used to characterize site in vivo:
mass spectrometry ( 3 , 4 , 7 , 9 , 11 , 16 , 18 ) , mutation of modification site ( 17 , 24 ) , phospho-antibody ( 1 , 2 , 5 , 6 , 10 , 12 , 13 , 14 , 15 , 19 , 20 , 21 , 23 , 26 , 27 , 28 , 29 ) , western blotting ( 1 , 2 , 5 , 6 , 10 , 12 , 13 , 14 , 15 , 17 , 26 , 27 , 29 )
Disease tissue studied:
breast cancer ( 7 , 13 ) , breast ductal carcinoma ( 7 ) , HER2 positive breast cancer ( 3 ) , luminal A breast cancer ( 3 ) , luminal B breast cancer ( 3 ) , breast cancer, surrounding tissue ( 3 ) , breast cancer, triple negative ( 3 ) , colorectal cancer ( 14 ) , colorectal carcinoma ( 14 ) , liver cancer ( 6 , 12 ) , lung cancer ( 14 ) , non-small cell lung cancer ( 14 ) , non-small cell squamous cell lung carcinoma ( 14 ) , melanoma skin cancer ( 4 ) , diabetes mellitus ( 13 ) , type 2 diabetes ( 13 )
Relevant cell line - cell type - tissue:
'muscle, skeletal' ( 16 ) , 'muscle, smooth'-'heart, artery' ( 10 ) , 293 (epithelial) ( 10 , 12 , 17 , 26 , 27 ) , 3T3 (fibroblast) [SHP-2 (mouse), homozygous knockout] ( 20 , 24 ) , 3T3 (fibroblast) ( 12 ) , 3T3-L1 (fibroblast) ( 12 ) , A549 (pulmonary) ( 14 ) , adipocyte ( 29 ) , adipocyte-adipose tissue ( 2 , 19 ) , breast ( 3 , 7 ) , CHO (fibroblast) [EphB1 (human), transfection] ( 23 ) , endothelial-retina ( 1 ) , H4IIe (hepatic) ( 12 ) , HCT116 (intestinal) ( 14 ) , HEK293T (epithelial) ( 17 ) , HeLa (cervical) ( 11 ) , hepatocyte-liver ( 6 ) , HepG2 (hepatic) ( 6 ) , liver ( 13 ) , M059K (glial) ( 18 ) , MDA-MB-453 (breast cell) ( 13 ) , MEF (fibroblast) ( 5 , 17 ) , muscle ( 21 , 28 ) , NCI-H1299 (pulmonary) ( 14 ) , NCI-H1650 (pulmonary) ( 14 ) , NCI-H1703 (squamous) ( 14 ) , NCI-H23 (pulmonary) ( 14 ) , NCI-H460 (pulmonary) ( 14 ) , vascular smooth muscle cell ('muscle, smooth') ( 15 ) , WM239A (melanocyte) ( 4 )

Upstream Regulation
Regulatory protein:
LKB1 (human) ( 14 ) , mTOR (human) ( 17 ) , p70S6K (human) ( 17 ) , P70S6KB (human) ( 17 ) , PPP4C (human) ( 6 ) , RHEB (human) ( 17 ) , TRBP (human) ( 5 ) , TSC1 (human) ( 13 ) , TSC1 (mouse) ( 17 ) , TSC2 (mouse) ( 17 )
Putative in vivo kinases:
p70S6K (mouse) ( 12 , 17 )
Kinases, in vitro:
p70S6K (human) ( 12 , 17 ) , PKCD (human) ( 22 , 25 )
Treatments:
AG1024 ( 10 ) , anisomycin ( 20 , 23 ) , calyculin_A ( 23 ) , glycyrrhizinic_acid ( 1 ) , high-fat diet ( 29 ) , high_glucose ( 1 ) , IGF-1 ( 10 ) , insulin ( 2 , 19 , 20 , 21 , 23 , 27 , 28 , 29 ) , Intralipid ( 28 ) , phorbol_ester ( 23 , 26 , 27 ) , rapamycin ( 15 , 17 , 19 , 20 ) , rosiglitazone ( 26 ) , salicylate ( 27 ) , siRNA ( 14 ) , SP600125 ( 6 , 20 , 27 ) , TNF ( 6 , 13 , 27 )

Downstream Regulation
Effects of modification on IRS1:
intracellular localization ( 17 ) , molecular association, regulation ( 24 ) , phosphorylation ( 19 )
Inhibit interaction with:
INSR (human) ( 24 )

References 

1

Liu L, Jiang Y, Steinle JJ (2017) Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins. PLoS One 12, e0178236
28542588   Curated Info

2

Rajan MR, et al. (2016) Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes. J Biol Chem 291, 15806-15819
27226562   Curated Info

3

Mertins P, et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534, 55-62
27251275   Curated Info

4

Stuart SA, et al. (2015) A Phosphoproteomic Comparison of B-RAFV600E and MKK1/2 Inhibitors in Melanoma Cells. Mol Cell Proteomics 14, 1599-615
25850435   Curated Info

5

Nakamura T, et al. (2015) A Critical Role for PKR Complexes with TRBP in Immunometabolic Regulation and eIF2α Phosphorylation in Obesity. Cell Rep 11, 295-307
25843719   Curated Info

6

Zhao H, et al. (2015) Protein phosphatase 4 (PP4) functions as a critical regulator in tumor necrosis factor (TNF)-α-induced hepatic insulin resistance. Sci Rep 5, 18093
26666849   Curated Info

7

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
24719451   Curated Info

8

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
23312004   Curated Info

9

Stokes MP, et al. (2012) PTMScan Direct: Identification and Quantification of Peptides from Critical Signaling Proteins by Immunoaffinity Enrichment Coupled with LC-MS/MS. Mol Cell Proteomics 11, 187-201
22322096   Curated Info

10

Perrault R, et al. (2011) Tyrosine kinase-independent activation of extracellular-regulated kinase (ERK) 1/2 by the insulin-like growth factor-1 receptor. Cell Signal 23, 739-46
21215800   Curated Info

11

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
21712546   Curated Info

12

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
18952604   Curated Info

13

Lee DF, et al. (2008) IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance. Int J Mol Med 22, 633-8
18949383   Curated Info

14

Zhong D, et al. (2008) LKB1 is necessary for Akt-mediated phosphorylation of proapoptotic proteins. Cancer Res 68, 7270-7
18794113   Curated Info

15

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
17908691   Curated Info

16

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
17360977   Curated Info

17

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
16914728   Curated Info

18

Stokes M (2005) CST Curation Set: 992; Year: 2005; Biosample1/Treatment/Isotope: cell line, M059K/UV/L, Biosample2/Treatment/Isotope: cell line, M059K/UV/H; Disease: glioblastoma; SILAC: Y; Specificities of Antibodies Used to Purify Peptides prior to LCMS:p[ST]
Curated Info

19

Danielsson A, Ost A, Nystrom FH, Strålfors P (2005) Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes. J Biol Chem 280, 34389-92
16129690   Curated Info

20

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
16099428   Curated Info

21

Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM (2005) Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54, 2351-9
16046301   Curated Info

22

del Rincón SV, et al. (2004) Retinoic acid mediates degradation of IRS-1 by the ubiquitin-proteasome pathway, via a PKC-dependant mechanism. Oncogene 23, 9269-79
15516986   Curated Info

23

Werner ED, et al. (2004) Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. J Biol Chem 279, 35298-305
15199052   Curated Info

24

Gao Z, et al. (2004) Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol 18, 2024-34
15143153   Curated Info

25

Greene MW, Morrice N, Garofalo RS, Roth RA (2004) Modulation of human insulin receptor substrate-1 tyrosine phosphorylation by protein kinase Cdelta. Biochem J 378, 105-16
14583092   Curated Info

26

Jiang G, et al. (2004) Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. Biochem J 377, 339-46
14556646   Curated Info

27

Jiang G, et al. (2003) Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. J Biol Chem 278, 180-6
12409308   Curated Info

28

Yu C, et al. (2002) Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277, 50230-6
12006582   Curated Info

29

Danielsson A, et al. Short-term overeating induces insulin resistance in fat cells in lean human subjects. Mol Med 15, 228-34
19593406   Curated Info