Ser312
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Home > Phosphorylation Site Page: > Ser312  -  IRS1 (human)

Site Information
tEsItAtsPAsMVGG   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447558

In vivo Characterization
Methods used to characterize site in vivo:
electrophoretic mobility shift ( 20 ) , mass spectrometry ( 1 , 3 , 4 , 7 , 12 , 18 ) , mutation of modification site ( 16 , 26 ) , phospho-antibody ( 6 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 17 , 19 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ) , western blotting ( 8 , 9 , 10 , 11 , 13 , 14 , 15 , 16 , 17 , 23 , 26 , 27 , 28 , 29 , 30 )
Disease tissue studied:
breast cancer ( 27 ) , colorectal cancer ( 9 ) , colorectal carcinoma ( 9 ) , liver cancer ( 6 , 11 , 26 , 28 ) , lung cancer ( 3 , 9 ) , non-small cell lung cancer ( 3 , 9 ) , non-small cell squamous cell lung carcinoma ( 9 ) , melanoma skin cancer ( 1 ) , polycystic ovary syndrome ( 20 )
Relevant cell line - cell type - tissue:
'granulosa, luteal' ( 8 ) , 'muscle, skeletal' ( 10 , 12 , 17 , 19 , 20 , 29 ) , 1321N1 (glial) ( 25 ) , 293 (epithelial) ( 16 , 18 ) , 293T (epithelial) ( 16 ) , A549 (pulmonary) ( 9 ) , adipocyte ( 30 ) , adipose tissue ( 13 ) , CHO (fibroblast) [EphB1 (human), transfection] ( 22 ) , H2077 (pulmonary) ( 3 ) , H322M (pulmonary) ( 3 ) , H4IIe (hepatic) ( 26 ) , HCC2279 (pulmonary) ( 3 ) , HCC827 (pulmonary) ( 3 ) , HCT116 (intestinal) ( 9 ) , HeLa (cervical) ( 7 ) , HepG2 (hepatic) ( 6 , 11 , 28 ) , Huh7 (hepatic) ( 11 ) , HUVEC (endothelial) ( 15 , 24 ) , L6 (myoblast) ( 19 ) , LCLC-103H (pulmonary) ( 3 ) , LLC-PK1 (epithelial) ( 14 ) , MCF-7 (breast cell) ( 27 ) , MEF (fibroblast) ( 16 ) , NCI-H1299 (pulmonary) ( 9 ) , NCI-H1650 (pulmonary) ( 9 ) , NCI-H1703 (squamous) ( 9 ) , NCI-H2172 (pulmonary) ( 3 ) , NCI-H23 (pulmonary) ( 9 ) , NCI-H460 (pulmonary) ( 9 ) , NCI-H520 (squamous) ( 3 ) , PC9 (pulmonary) ( 3 ) , RIN (epithelial) ( 23 ) , T47D (breast cell) ( 27 ) , WM239A (epidermal) ( 1 )

Upstream Regulation
Regulatory protein:
IKKB (human) ( 10 ) , JNK1 (human) ( 15 ) , JNK2 (human) ( 15 ) , LKB1 (human) ( 9 ) , mTOR (human) ( 16 ) , p70S6K (human) ( 16 , 21 ) , P70S6KB (human) ( 16 ) , RHEB (human) ( 16 ) , TSC1 (mouse) ( 16 ) , TSC2 (mouse) ( 16 )
Putative in vivo kinases:
JNK1 (human) ( 23 ) , p70S6K (mouse) ( 16 )
Kinases, in vitro:
IKKB (human) ( 28 )
Treatments:
14,15-EETs ( 6 ) , 15d-PGJ2 ( 28 ) , amino_acids ( 19 ) , angiotensin ( 24 ) , anisomycin ( 22 ) , azaserine ( 23 ) , calyculin_A ( 22 , 28 ) , carbachol ( 25 ) , dexamethasone ( 14 ) , dinoprost ( 8 ) , glucosamine ( 23 ) , glucose ( 23 ) , high-fat diet ( 30 ) , IGF-1 ( 27 ) , IL-6 ( 11 , 15 ) , insulin ( 10 , 12 , 13 , 15 , 17 , 19 , 20 , 21 , 22 , 24 , 25 , 26 , 29 , 30 ) , JNK_inhibitor_I ( 15 , 23 ) , losartan ( 24 ) , LY294002 ( 11 , 26 , 27 ) , okadaic_acid ( 25 ) , palmitate ( 6 ) , PD98059 ( 15 , 24 ) , phorbol_ester ( 22 ) , rapamycin ( 8 , 16 , 19 , 26 ) , siRNA ( 9 , 10 , 15 , 21 ) , SP600125 ( 11 , 26 ) , taxol ( 27 ) , TNF ( 10 , 11 , 28 ) , U0126 ( 8 , 26 ) , virus infection ( 11 )

Downstream Regulation
Effects of modification on IRS1:
intracellular localization ( 16 ) , molecular association, regulation ( 28 ) , protein degradation ( 26 )
Effects of modification on biological processes:
apoptosis, altered ( 9 )
Inhibit interaction with:
IKKA (human) ( 28 ) , IKKB (human) ( 28 )

References 

1

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

2

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

3

Klammer M, et al. (2012) Phosphosignature predicts dasatinib response in non-small cell lung cancer. Mol Cell Proteomics 11, 651-68
22617229   Curated Info

4

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

5

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
22424773   Curated Info

6

Skepner JE, et al. (2011) Chronic treatment with epoxyeicosatrienoic acids modulates insulin signaling and prevents insulin resistance in hepatocytes. Prostaglandins Other Lipid Mediat 94, 3-8
21040800   Curated Info

7

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

8

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
20160123   Curated Info

9

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

10

Austin RL, et al. (2008) siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle. Diabetes 57, 2066-73
18443205   Curated Info

11

Banerjee S, et al. (2008) Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol 82, 2606-12
18160431   Curated Info

12

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

13

Bashan N, et al. (2007) Mitogen-activated protein kinases, inhibitory-kappaB kinase, and insulin signaling in human omental versus subcutaneous adipose tissue in obesity. Endocrinology 148, 2955-62
17317777   Curated Info

14

Wang X, Hu J, Price SR (2007) Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells. Am J Physiol Cell Physiol 292, C1874-9
17229808   Curated Info

15

Andreozzi F, et al. (2007) Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. Mol Cell Biol 27, 2372-83
17242212   Curated Info

16

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

17

Bouzakri K, et al. (2006) IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients. Diabetes 55, 785-91
16505244   Curated Info

18

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
16020478   Curated Info

19

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
16123357   Curated Info

20

Corbould A, et al. (2005) Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 288, E1047-54
15613682   Curated Info

21

Um SH, et al. (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200-5
15306821   Curated Info

22

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

23

Andreozzi F, et al. (2004) Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cells. Endocrinology 145, 2845-57
15001544   Curated Info

24

Andreozzi F, et al. (2004) Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res 94, 1211-8
15044323   Curated Info

25

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
14769130   Curated Info

26

Greene MW, et al. (2003) Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. J Biol Chem 278, 8199-211
12510059   Curated Info

27

Mamay CL, et al. (2003) An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer. Oncogene 22, 602-14
12555073   Curated Info

28

Gao Z, et al. (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277, 48115-21
12351658   Curated Info

29

Rui L, et al. (2001) Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 107, 181-9
11160134   Curated Info

30

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