Ser166
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Home > Phosphorylation Site Page: > Ser166  -  MDM2 (human)

Site Information
SsRRRAIsEtEENsD   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 448130

In vivo Characterization
Methods used to characterize site in vivo:
[32P] bio-synthetic labeling ( 45 , 53 ) , immunoprecipitation ( 2 , 3 , 16 ) , mass spectrometry ( 4 , 8 , 10 , 11 , 12 , 13 , 15 , 17 , 18 , 20 , 23 , 24 , 25 , 26 , 27 , 29 , 33 , 53 ) , mass spectrometry (in vitro) ( 23 ) , mutation of modification site ( 1 , 2 , 16 , 34 , 39 , 43 , 45 , 46 , 47 , 50 , 52 , 53 ) , phospho-antibody ( 1 , 6 , 7 , 9 , 14 , 21 , 22 , 28 , 30 , 31 , 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 49 , 51 ) , phosphopeptide mapping ( 45 ) , western blotting ( 1 , 2 , 3 , 6 , 7 , 9 , 14 , 16 , 21 , 22 , 28 , 30 , 31 , 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 49 )
Disease tissue studied:
bone cancer ( 31 , 34 , 43 , 45 , 47 ) , brain cancer ( 46 ) , glioblastoma ( 46 ) , glioma ( 46 ) , breast cancer ( 11 , 16 , 17 , 28 , 31 , 38 , 39 , 42 , 45 ) , breast adenocarcinoma ( 31 ) , breast ductal carcinoma ( 11 ) , HER2 positive breast cancer ( 4 ) , luminal A breast cancer ( 4 ) , luminal B breast cancer ( 4 ) , breast cancer, surrounding tissue ( 4 ) , breast cancer, triple negative ( 4 , 11 , 31 ) , colorectal cancer ( 7 , 14 , 47 ) , colorectal carcinoma ( 7 , 14 , 47 ) , gastric cancer ( 20 , 24 , 25 , 26 ) , gastric carcinoma ( 20 , 24 , 25 , 26 ) , gestational cancer ( 21 ) , gestational trophoblastic choriocarcinoma ( 21 ) , kidney cancer ( 22 , 28 ) , liver cancer ( 9 , 40 , 44 ) , hepatocellular carcinoma ( 9 ) , lung cancer ( 1 , 3 , 12 , 17 , 34 , 39 , 40 , 49 ) , non-small cell lung cancer ( 1 , 3 , 17 , 34 , 39 , 49 ) , non-small cell lung adenocarcinoma ( 12 ) , lymphoma ( 14 ) , Burkitt's lymphoma ( 14 ) , neuroblastoma ( 2 ) , prostate cancer ( 31 , 35 , 46 ) , melanoma skin cancer ( 8 )
Relevant cell line - cell type - tissue:
22Rv1 (prostate cell) ( 35 ) , 293 (epithelial) [MDM2 (human)] ( 46 ) , 293 (epithelial) ( 28 , 53 ) , 3T3 (fibroblast) [SHP-2 (mouse), homozygous knockout] ( 52 ) , A549 (pulmonary) ( 40 ) , BJ (fibroblast) ( 41 ) , breast ( 4 , 11 ) , BT-474 (breast cell) ( 39 ) , BT-549 (breast cell) ( 17 ) , C3H10T1/2 (fibroblast) ( 36 ) , COS (fibroblast) ( 49 ) , DLD1 (intestinal) ( 7 ) , embryo ( 30 ) , H2077 (pulmonary) ( 17 ) , H322M (pulmonary) ( 17 ) , HCC1937 (breast cell) ( 17 ) , HCC827 (pulmonary) ( 17 ) , HCT116 (intestinal) ( 7 , 47 ) , HEK293T (epithelial) ( 6 , 16 , 23 , 39 , 51 ) , HeLa (cervical) ( 10 ) , Hep 3B2.1-7 (hepatic) ( 9 ) , HepG2 (hepatic) ( 9 , 40 , 44 ) , HOP62 (pulmonary) ( 17 ) , Hs 578T (breast cell) ( 39 ) , HUES-7 ('stem, embryonic') ( 29 ) , IMR-90 (fibroblast) ( 41 ) , JEG-3 (uterine) ( 21 ) , Jurkat (T lymphocyte) ( 13 , 27 , 33 ) , K562 (erythroid) ( 15 ) , kidney ( 22 , 28 ) , LCLC-103H (pulmonary) ( 17 ) , liver ( 40 ) , LNCaP (prostate cell) ( 31 , 35 , 46 ) , LOU-NH91 (squamous) ( 17 ) , lung ( 12 ) , MCF-10A (breast cell) ( 42 ) , MCF-7 (breast cell) ( 17 , 28 , 31 , 38 , 39 , 45 , 53 ) , MDA-MB-231 (breast cell) ( 17 , 39 ) , MDA-MB-468 (breast cell) ( 31 ) , MDST8 (intestinal) ( 14 ) , MEF (fibroblast) ( 34 , 36 , 43 , 49 ) , MEF (fibroblast) [IGF1R (mouse)] ( 52 ) , MEF (fibroblast) [MAPKAPK2 (mouse)] ( 43 ) , MKN-45 (gastric) ( 20 , 24 , 25 , 26 ) , MRC5 (fibroblast) ( 50 ) , MSU1.1 (fibroblast) ( 32 ) , Namalwa (B lymphocyte) ( 14 ) , NCI-H1299 (pulmonary) ( 1 , 3 , 34 , 49 ) , NCI-H157 (pulmonary) ( 39 ) , NCI-H322 (pulmonary) ( 17 ) , NCI-H3255 (pulmonary) ( 18 ) , NCI-H460 (pulmonary) ( 17 ) , PH3MT (fibroblast) [HRas (human), transfection] ( 32 ) , Saos-2 (bone cell) ( 47 , 53 ) , SHEP (neuron) ( 2 ) , SJSA-1 (bone cell) ( 45 ) , SKBr3 (breast cell) ( 39 ) , SKNSH (neural crest) ( 2 ) , SNU-398 (hepatic) ( 9 ) , SW480 (intestinal) ( 7 ) , Swiss 3T3 (fibroblast) ( 49 ) , synoviocyte-synovium ( 37 ) , T lymphocyte-blood ( 37 ) , U2OS (bone cell) [GR (human)] ( 45 , 51 ) , U2OS (bone cell) [MDM2 (human)] ( 43 ) , U2OS (bone cell) ( 31 , 34 ) , U87MG (glial) ( 46 ) , WI-38 (fibroblast) ( 31 ) , WM239A (melanocyte) ( 8 ) , ZR-75-1 (breast cell) ( 39 )

Upstream Regulation
Regulatory protein:
Akt1 (human) ( 39 , 40 ) , Akt2 (human) ( 39 ) , Akt3 (human) ( 39 ) , ARAF (human) ( 41 ) , CCNG1 (human) ( 9 ) , CCNG1 (mouse) ( 49 ) , GRP78 (human) ( 21 ) , HIF2A (human) ( 28 ) , NF1 (human) ( 41 ) , NOTCH3 (human) ( 9 ) , PHLDA3 (human) ( 31 ) , PHLPP (human) ( 39 ) , PHLPP2 (human) ( 39 ) , PPP2CA (human) ( 14 ) , SMO (mouse) ( 36 ) , SPRY2 (human) ( 32 )
Putative in vivo kinases:
Akt1 (human) ( 14 , 46 , 51 , 52 , 53 ) , MAPKAPK2 (mouse) ( 43 ) , Pim1 (human) ( 34 )
Kinases, in vitro:
Akt1 (human) ( 45 , 46 , 50 , 52 , 53 ) , CK1D (human) ( 23 ) , DAPK3 (human) ( 48 ) , MAPKAPK2 (human) ( 43 ) , Pim1 (human) ( 34 ) , PKM (human) ( 3 )
Putative upstream phosphatases:
PPP2CA (mouse) ( 49 )
Treatments:
aminoflavone ( 38 ) , anisomycin ( 40 , 43 ) , BPDE ( 42 ) , CDCA ( 40 ) , cycloheximide ( 36 ) , deguelin ( 30 ) , deoxycholic_acid ( 40 ) , EGF ( 32 ) , etoposide ( 40 ) , H2O2 ( 40 ) , IGF-1 ( 46 , 53 ) , insulin ( 40 ) , isosilybin_B ( 35 ) , lenalidomide ( 14 ) , LY294002 ( 28 , 30 , 34 , 35 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ) , MG132 ( 7 ) , NSC59984 ( 7 ) , nutlin-3 ( 7 ) , PAF ( 30 ) , PD90059 ( 40 ) , PD98059 ( 40 , 42 ) , pravastatin ( 44 ) , rapamycin ( 40 , 44 ) , SB203580 ( 42 ) , serum ( 43 , 45 , 51 ) , serum_starvation ( 45 ) , Shh ( 36 ) , siRNA ( 39 ) , tautomycin ( 6 ) , TGF-alpha ( 40 ) , tunicamycin ( 21 ) , U0126 ( 40 ) , UV ( 43 ) , vemurafenib ( 8 ) , wortmannin ( 40 , 44 )

Downstream Regulation
Effects of modification on MDM2:
activity, induced ( 6 , 47 ) , enzymatic activity, induced ( 43 ) , intracellular localization ( 2 , 3 , 14 , 22 , 52 , 53 ) , molecular association, regulation ( 1 , 34 , 52 ) , protein degradation ( 2 ) , protein stabilization ( 14 , 32 , 34 , 46 ) , ubiquitination ( 34 )
Effects of modification on biological processes:
apoptosis, altered ( 43 , 52 ) , carcinogenesis, induced ( 1 ) , cell cycle regulation ( 43 ) , cell growth, induced ( 1 ) , signaling pathway regulation ( 1 ) , transcription, induced ( 2 ) , translation, altered ( 47 ) , translation, induced ( 1 )
Induce interaction with:
ARF1 (human) ( 34 ) , RNA ( 1 ) , p300 (human) ( 52 )

Disease / Diagnostics Relevance
Relevant diseases:
kidney cancer ( 28 ) , mantle cell lymphoma ( 34 )

References 

1

Gnanasundram SV, et al. (2020) MDM2's dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities. Nucleic Acids Res
32453417   Curated Info

2

Liu T, et al. (2017) FKBP12 enhances sensitivity to chemotherapy-induced cancer cell apoptosis by inhibiting MDM2. Oncogene 36, 1678-1686
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3

Riscal R, et al. (2016) Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53. Mol Cell 62, 890-902
27264869   Curated Info

4

Mertins P, et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534, 55-62
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5

Boeing S, et al. (2016) Multiomic Analysis of the UV-Induced DNA Damage Response. Cell Rep 15, 1597-1610
27184836   Curated Info

6

Liu X, et al. (2016) Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation. Oncotarget 7, 1754-64
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7

Zhang S, et al. (2015) Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer Res 75, 3842-52
26294215   Curated Info

8

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

9

Giovannini C, et al. (2014) Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma. Oncotarget 5, 10607-20
25431954   Curated Info

10

Sharma K, et al. (2014) Ultradeep human phosphoproteome reveals a distinct regulatory nature of Tyr and Ser/Thr-based signaling. Cell Rep 8, 1583-94
25159151   Curated Info

11

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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12

Schweppe DK, Rigas JR, Gerber SA (2013) Quantitative phosphoproteomic profiling of human non-small cell lung cancer tumors. J Proteomics 91, 286-96
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13

Mertins P, et al. (2013) Integrated proteomic analysis of post-translational modifications by serial enrichment. Nat Methods 10, 634-7
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14

Wei S, et al. (2013) Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. Oncogene 32, 1110-20
22525275   Curated Info

15

Zhou H, et al. (2013) Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res 12, 260-71
23186163   Curated Info

16

Sanchez M, Picard N, Sauvé K, Tremblay A (2013) Coordinate regulation of estrogen receptor β degradation by Mdm2 and CREB-binding protein in response to growth signals. Oncogene 32, 117-26
22349818   Curated Info

17

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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18

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
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19

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

20

Guo A (2011) CST Curation Set: 11299; Year: 2011; Biosample/Treatment: cell line, MKN-45/untreated; Disease: gastric carcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY])
Curated Info

21

Yung HW, Charnock-Jones DS, Burton GJ (2011) Regulation of AKT phosphorylation at Ser473 and Thr308 by endoplasmic reticulum stress modulates substrate specificity in a severity dependent manner. PLoS One 6, e17894
21445305   Curated Info

22

Lai KP, et al. (2010) S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. EMBO J 29, 2994-3006
20657550   Curated Info

23

Inuzuka H, et al. (2010) Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell 18, 147-59
20708156   Curated Info

24

Moritz A (2010) CST Curation Set: 10238; Year: 2010; Biosample/Treatment: cell line, MKN-45/DMSO; Disease: gastric carcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY]
Curated Info

25

Moritz A (2010) CST Curation Set: 10020; Year: 2010; Biosample/Treatment: cell line, MKN-45/DMSO; Disease: gastric carcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY])
Curated Info

26

Moritz A (2010) CST Curation Set: 9374; Year: 2010; Biosample/Treatment: cell line, MKN-45/DMSO; Disease: gastric carcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY])
Curated Info

27

Moritz A (2010) CST Curation Set: 8838; Year: 2010; Biosample/Treatment: cell line, Jurkat/pervanadate; Disease: T cell leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: pY Antibodies Used to Purify Peptides prior to LCMS: Phospho-Tyrosine Mouse mAb (P-Tyr-100) Cat#: 9411, PTMScan(R) Phospho-Tyr Motif (Y*) Immunoaffinity Beads Cat#: 1991
Curated Info

28

Roberts AM, et al. (2009) Suppression of hypoxia-inducible factor 2alpha restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells. Cancer Res 69, 9056-64
19920202   Curated Info

29

Van Hoof D, et al. (2009) Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell 5, 214-26
19664995   Curated Info

30

Jin XL, Chandrakanthan V, Morgan HD, O'Neill C (2009) Preimplantation embryo development in the mouse requires the latency of TRP53 expression, which is induced by a ligand-activated PI3 kinase/AKT/MDM2-mediated signaling pathway. Biol Reprod 81, 234-42
19630168   Curated Info

31

Kawase T, et al. (2009) PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell 136, 535-50
19203586   Curated Info

32

Lito P, et al. (2009) Sprouty 2 regulates DNA damage-induced apoptosis in Ras-transformed human fibroblasts. J Biol Chem 284, 848-54
19008219   Curated Info

33

Mayya V, et al. (2009) Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal 2, ra46
19690332   Curated Info

34

Hogan C, et al. (2008) Elevated levels of oncogenic protein kinase Pim-1 induce the p53 pathway in cultured cells and correlate with increased Mdm2 in mantle cell lymphoma. J Biol Chem 283, 18012-23
18467333   Curated Info

35

Deep G, Oberlies NH, Kroll DJ, Agarwal R (2008) Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway. Oncogene 27, 3986-98
18332867   Curated Info

36

Abe Y, et al. (2008) Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci U S A 105, 4838-43
18359851   Curated Info

37

Singh K, et al. (2008) Synoviocyte stimulation by the LFA-1-intercellular adhesion molecule-2-Ezrin-Akt pathway in rheumatoid arthritis. J Immunol 180, 1971-8
18209096   Curated Info

38

Meng LH, Kohn KW, Pommier Y (2007) Dose-response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686,288). Oncogene 26, 4806-16
17297446   Curated Info

39

Brognard J, Sierecki E, Gao T, Newton AC (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 25, 917-31
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40

Malmlöf M, Roudier E, Högberg J, Stenius U (2007) MEK-ERK-mediated phosphorylation of Mdm2 at Ser-166 in hepatocytes. Mdm2 is activated in response to inhibited Akt signaling. J Biol Chem 282, 2288-96
17107963   Curated Info

41

Courtois-Cox S, et al. (2006) A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10, 459-72
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42

Burdick AD, Ivnitski-Steele ID, Lauer FT, Burchiel SW (2006) PYK2 mediates anti-apoptotic AKT signaling in response to benzo[a]pyrene diol epoxide in mammary epithelial cells. Carcinogenesis 27, 2331-40
16774943   Curated Info

43

Weber HO, et al. (2005) HDM2 phosphorylation by MAPKAP kinase 2. Oncogene 24, 1965-72
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44

Pääjärvi G, et al. (2005) HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage. FASEB J 19, 476-8
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45

Milne D, et al. (2004) A novel site of AKT-mediated phosphorylation in the human MDM2 onco-protein. FEBS Lett 577, 270-6
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46

Feng J, et al. (2004) Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J Biol Chem 279, 35510-7
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47

Bárdos JI, Chau NM, Ashcroft M (2004) Growth factor-mediated induction of HDM2 positively regulates hypoxia-inducible factor 1alpha expression. Mol Cell Biol 24, 2905-14
15024078   Curated Info

48

Burch LR, et al. (2004) Phage-peptide display identifies the interferon-responsive, death-activated protein kinase family as a novel modifier of MDM2 and p21WAF1. J Mol Biol 337, 115-28
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49

Okamoto K, et al. (2002) Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell 9, 761-71
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50

Ashcroft M, et al. (2002) Phosphorylation of HDM2 by Akt. Oncogene 21, 1955-62
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51

Gottlieb TM, et al. (2002) Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21, 1299-303
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52

Zhou BP, et al. (2001) HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3, 973-82
11715018   Curated Info

53

Mayo LD, Donner DB (2001) A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 98, 11598-603
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