Ser139
Javascript is not enabled on this browser. This site will not work properly without Javascript.
PhosphoSitePlus Homepage PhosphoSitePlus® v6.5.9.3
Powered by Cell Signaling Technology
Home > Phosphorylation Site Page: > Ser139  -  H2AX (mouse)

Site Information
GkKAsQAsQEy____   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 448841

In vivo Characterization
Methods used to characterize site in vivo:
2D analysis ( 41 ) , [32P] bio-synthetic labeling ( 41 ) , electrophoretic mobility shift ( 44 ) , flow cytometry ( 25 ) , immunoassay ( 1 ) , immunoprecipitation ( 2 ) , mass spectrometry ( 2 , 5 , 7 , 10 , 12 , 14 , 15 , 18 , 22 , 24 ) , microscopy-colocalization with upstream kinase ( 36 ) , mutation of modification site ( 4 , 33 , 37 , 41 ) , peptide sequencing ( 38 ) , phospho-antibody ( 1 , 2 , 3 , 4 , 9 , 11 , 13 , 19 , 20 , 21 , 23 , 25 , 26 , 27 , 28 , 29 , 33 , 34 , 35 , 36 , 37 , 39 , 40 , 42 , 43 , 44 , 45 , 46 ) , western blotting ( 2 , 3 , 4 , 9 , 13 , 19 , 20 , 21 , 23 , 25 , 26 , 27 , 28 , 29 , 33 , 34 , 35 , 37 , 38 , 43 , 44 , 45 )
Disease tissue studied:
breast cancer ( 38 ) , leukemia ( 15 ) , acute myelogenous leukemia ( 15 )
Relevant cell line - cell type - tissue:
'3T3-L1, differentiated' (adipocyte) ( 7 , 12 ) , 'brain, embryonic' ( 21 , 36 ) , 'kidney, inner medulla' ( 45 ) , 'stem, embryonic' ( 22 ) , 'stem, neural' ( 1 ) , 293 (epithelial) ( 33 , 37 ) , 32Dcl3 (myeloid) [FLT3 (mouse), transfection, chimera with human FLT3-ITD mutant (corresponding to wild type P36888 ( 24 ) , 32Dcl3 (myeloid) ( 24 ) , 3T3 (fibroblast) ( 25 , 28 , 38 ) , BJ (fibroblast) ( 4 ) , blood ( 15 ) , ES (stem) ( 33 ) , germ cell-testis ( 40 ) , JB6 RT101 (epidermal) ( 37 ) , keratinocyte ( 23 ) , kidney ( 27 ) , liver ( 5 , 14 , 27 ) , liver [leptin (mouse), homozygous knockout] ( 14 ) , lung ( 18 ) , MCF-7 (breast cell) ( 38 ) , MEF (fibroblast) ( 2 , 3 , 9 , 19 , 23 , 28 , 29 , 34 , 35 , 37 , 43 , 44 , 46 ) , MEF (fibroblast) [IGF1R (mouse)] ( 41 , 42 ) , MEF (fibroblast) [PTPN2 (mouse), homozygous knockout] ( 26 ) , MEF (fibroblast) [TOP3B (mouse)] ( 29 ) , mIMCD-3 (epithelial) ( 45 ) , pancreas ( 13 ) , spermatocytes [ATR (mouse), transgenic] ( 11 ) , spleen [PPM1D (mouse), homozygous knockout] ( 20 ) , stromal ( 10 ) , testis ( 18 ) , thymus ( 39 ) , vascular smooth muscle cell ('muscle, smooth') ( 4 )

Upstream Regulation
Regulatory protein:
ATM (mouse) ( 27 ) , ATR (mouse) ( 11 , 25 , 44 ) , DNAPK (mouse) ( 27 ) , ERK2 (mouse) ( 37 ) , HDAC2 (mouse) ( 28 ) , HDAC3 (mouse) ( 28 ) , JNK1 (mouse) ( 37 ) , JNK2 (mouse) ( 37 ) , MAPKAPK2 (mouse) ( 35 ) , MDM4 (mouse) ( 9 ) , P38B (mouse) ( 37 ) , PHF2 (mouse) ( 1 ) , POT1 (mouse) ( 19 ) , PTPN2 (human) ( 26 ) , ROCK1 (human) ( 32 ) , S6 (mouse) ( 13 ) , SMO (mouse) ( 30 ) , TOP3B (mouse) ( 29 ) , TREX1 (mouse) ( 34 )
Putative in vivo kinases:
ATM (mouse) ( 46 ) , JNK1 (mouse) ( 37 ) , JNK2 (mouse) ( 37 )
Kinases, in vitro:
ATM (mouse) ( 46 ) , JNK1 (mouse) ( 37 ) , JNK2 (mouse) ( 37 )
Putative upstream phosphatases:
PPM1D (mouse) ( 20 )
Treatments:
adriamycin ( 35 ) , aphidicolin ( 26 , 44 ) , bleomycin ( 46 ) , calyculin_A ( 29 ) , camptothecin ( 42 ) , cisplatin ( 35 ) , etoposide ( 21 , 46 ) , HA-1077 ( 32 ) , hydroxyurea ( 38 ) , hypoxia ( 43 ) , insulin ( 12 ) , ionizing_radiation ( 9 , 27 , 28 , 29 , 34 , 39 , 40 , 45 , 46 ) , KU-55933 ( 25 ) , low_pH ( 42 ) , LY294002 ( 12 ) , neocarzinostatin ( 46 ) , osmotic_stress ( 45 ) , PD98059 ( 37 ) , SB202190 ( 37 , 45 ) , serum ( 25 ) , siRNA ( 25 , 28 , 35 , 37 ) , SP600125 ( 37 ) , tempol ( 39 ) , thymidine ( 26 ) , U0126 ( 38 ) , UV ( 23 , 25 , 37 ) , VM-26 ( 42 ) , wortmannin ( 46 )

Downstream Regulation
Effects of modification on H2AX:
activity, induced ( 37 , 46 ) , molecular association, regulation ( 33 )
Effects of modification on biological processes:
apoptosis, induced ( 37 )
Induce interaction with:
MDC1 (mouse) ( 33 )

References 

1

Pappa S, et al. (2019) PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors. Proc Natl Acad Sci U S A 116, 19464-19473
31488723   Curated Info

2

Segura-Bayona S, et al. (2017) Differential requirements for Tousled-like kinases 1 and 2 in mammalian development. Cell Death Differ 24, 1872-1885
28708136   Curated Info

3

Garzón J, et al. (2017) Shortage of dNTPs underlies altered replication dynamics and DNA breakage in the absence of the APC/C cofactor Cdh1. Oncogene 36, 5808-5818
28604743   Curated Info

4

Latella L, et al. (2017) DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes Dev 31, 648-659
28446595   Curated Info

5

Robles MS, Humphrey SJ, Mann M (2017) Phosphorylation Is a Central Mechanism for Circadian Control of Metabolism and Physiology. Cell Metab 25, 118-127
27818261   Curated Info

6

Sacco F, et al. (2016) Glucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion. Nat Commun 7, 13250
27841257   Curated Info

7

Minard AY, et al. (2016) mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes. Cell Rep 17, 29-36
27681418   Curated Info

8

Sheikh BN, et al. (2015) MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway. Oncogene 34, 5807-20
25772242   Curated Info

9

Carrillo AM, Bouska A, Arrate MP, Eischen CM (2015) Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 34, 846-56
24608433   Curated Info

10

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

11

Royo H, et al. (2013) ATR acts stage specifically to regulate multiple aspects of mammalian meiotic silencing. Genes Dev 27, 1484-94
23824539   Curated Info

12

Humphrey SJ, et al. (2013) Dynamic Adipocyte Phosphoproteome Reveals that Akt Directly Regulates mTORC2. Cell Metab 17, 1009-20
23684622   Curated Info

13

Khalaileh A, et al. (2013) Phosphorylation of ribosomal protein S6 attenuates DNA damage and tumor suppression during development of pancreatic cancer. Cancer Res 73, 1811-20
23361300   Curated Info

14

Grimsrud PA, et al. (2012) A quantitative map of the liver mitochondrial phosphoproteome reveals posttranslational control of ketogenesis. Cell Metab 16, 672-83
23140645   Curated Info

15

Trost M, et al. (2012) Posttranslational regulation of self-renewal capacity: insights from proteome and phosphoproteome analyses of stem cell leukemia. Blood 120, e17-27
22802335   Curated Info

16

White D, et al. (2012) The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation. Mol Cancer Res 10, 401-14
22205726   Curated Info

17

Wu CY, et al. (2011) Critical role of monoubiquitination of histone H2AX protein in histone H2AX phosphorylation and DNA damage response. J Biol Chem 286, 30806-15
21690091   Curated Info

18

Huttlin EL, et al. (2010) A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143, 1174-89
21183079   Curated Info

19

Gong Y, de Lange T (2010) A Shld1-controlled POT1a provides support for repression of ATR signaling at telomeres through RPA exclusion. Mol Cell 40, 377-87
21070964   Curated Info

20

Moon SH, et al. (2010) Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. J Biol Chem 285, 12935-47
20118229   Curated Info

21

Nam C, Doi K, Nakayama H (2010) Etoposide induces G2/M arrest and apoptosis in neural progenitor cells via DNA damage and an ATM/p53-related pathway. Histol Histopathol 25, 485-93
20183801   Curated Info

22

Tucker M (2010) CST Curation Set: 9081; Year: 2010; Biosample/Treatment: cell line, embryonic stem cells (mouse)/untreated; Disease: -; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[ST]Q Antibodies Used to Purify Peptides prior to LCMS: Phospho(Ser/Thr) ATM/ATR Substrate Antibody (polyAB) Cat#: 3005, PTMScan(R) Phospho-ATM/ATR Substrate Motif (pS/pTQ) Immunoaffinity Beads Cat#: 1980
Curated Info

23

LaGory EL, Sitailo LA, Denning MF (2010) The protein kinase Cdelta catalytic fragment is critical for maintenance of the G2/M DNA damage checkpoint. J Biol Chem 285, 1879-87
19917613   Curated Info

24

Choudhary C, et al. (2009) Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell 36, 326-39
19854140   Curated Info

25

Hitomi M, Yang K, Stacey AW, Stacey DW (2008) Phosphorylation of cyclin D1 regulated by ATM or ATR controls cell cycle progression. Mol Cell Biol 28, 5478-93
18606783   Curated Info

26

Shields BJ, et al. (2008) DNA replication stalling attenuates tyrosine kinase signaling to suppress S phase progression. Cancer Cell 14, 166-79
18691551   Curated Info

27

Koike M, Mashino M, Sugasawa J, Koike A (2008) Histone H2AX phosphorylation independent of ATM after X-irradiation in mouse liver and kidney in situ. J Radiat Res (Tokyo) 49, 445-9
18413980   Curated Info

28

Bhaskara S, et al. (2008) Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell 30, 61-72
18406327   Curated Info

29

Mohanty S, et al. (2008) Defective p53 engagement after the induction of DNA damage in cells deficient in topoisomerase 3beta. Proc Natl Acad Sci U S A 105, 5063-8
18367668   Curated Info

30

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

31

Shimada M, et al. (2008) Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. Cell 132, 221-32
18243098   Curated Info

32

Ongusaha PP, et al. (2008) Identification of ROCK1 as an upstream activator of the JIP-3 to JNK signaling axis in response to UVB damage. Sci Signal 1, ra14
19036714   Curated Info

33

Xie A, et al. (2007) Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair. Mol Cell 28, 1045-57
18158901   Curated Info

34

Yang YG, Lindahl T, Barnes DE (2007) Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873-86
18045533   Curated Info

35

Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB (2007) p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11, 175-89
17292828   Curated Info

36

Cang Y, et al. (2006) Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells. Cell 127, 929-40
17129780   Curated Info

37

Lu C, et al. (2006) Cell apoptosis: requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. Mol Cell 23, 121-32
16818236   Curated Info

38

Wu D, et al. (2006) ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function. Oncogene 25, 1153-64
16186792   Curated Info

39

Erker L, et al. (2005) Cancer chemoprevention by the antioxidant tempol acts partially via the p53 tumor suppressor. Hum Mol Genet 14, 1699-708
15888486   Curated Info

40

Forand A, Dutrillaux B, Bernardino-Sgherri J (2004) Gamma-H2AX expression pattern in non-irradiated neonatal mouse germ cells and after low-dose gamma-radiation: relationships between chromatid breaks and DNA double-strand breaks. Biol Reprod 71, 643-9
15115728   Curated Info

41

Celeste A, et al. (2003) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 5, 675-9
12792649   Curated Info

42

Xiao H, Li TK, Yang JM, Liu LF (2003) Acidic pH induces topoisomerase II-mediated DNA damage. Proc Natl Acad Sci U S A 100, 5205-10
12692309   Curated Info

43

Hammond EM, Dorie MJ, Giaccia AJ (2003) ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 278, 12207-13
12519769   Curated Info

44

Brown EJ, Baltimore D (2003) Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev 17, 615-28
12629044   Curated Info

45

Dmitrieva NI, Bulavin DV, Fornace AJ, Burg MB (2002) Rapid activation of G2/M checkpoint after hypertonic stress in renal inner medullary epithelial (IME) cells is protective and requires p38 kinase. Proc Natl Acad Sci U S A 99, 184-9
11756692   Curated Info

46

Burma S, et al. (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276, 42462-7
11571274   Curated Info