Ser181
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Home > Phosphorylation Site Page: > Ser181  -  IKKB (human)

Site Information
DQGsLCtsFVGTLQy   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447489

In vivo Characterization
Methods used to characterize site in vivo:
[32P] bio-synthetic labeling ( 31 , 35 , 37 ) , immunoprecipitation ( 2 , 17 , 19 , 20 ) , mass spectrometry ( 2 , 9 ) , mutation of modification site ( 2 , 7 , 26 , 31 , 32 , 35 , 37 , 39 ) , phospho-antibody ( 1 , 2 , 3 , 5 , 12 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 28 , 29 , 30 , 31 , 32 , 33 ) , phosphopeptide mapping ( 37 ) , western blotting ( 1 , 2 , 3 , 5 , 12 , 14 , 15 , 16 , 17 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 30 , 31 , 33 , 39 )
Disease tissue studied:
bone cancer ( 12 ) , cervical cancer ( 15 ) , cervical squamous cell carcinoma ( 15 ) , colorectal cancer ( 12 ) , colorectal carcinoma ( 12 ) , endometrial cancer ( 26 ) , endometrial adenocarcinoma ( 26 ) , lung cancer ( 5 , 18 , 22 , 25 ) , non-small cell lung cancer ( 5 , 22 ) , non-small cell lung adenocarcinoma ( 5 ) , lymphoma ( 2 , 7 ) , B cell lymphoma ( 2 , 7 ) , non-Hodgkin's lymphoma ( 2 ) , follicular lymphoma ( 2 ) , fibrosarcoma of soft tissue ( 24 )
Relevant cell line - cell type - tissue:
293 (epithelial) ( 9 , 19 , 21 , 30 , 33 ) , 293T (epithelial) ( 16 , 17 , 32 , 35 ) , A549 (pulmonary) ( 18 , 22 , 25 ) , adipose tissue ( 23 ) , DT40 (B lymphocyte) ( 7 ) , endometrium ( 26 ) , HaCaT (keratinocyte) ( 1 ) , HCT116 (intestinal) ( 12 ) , HeLa (cervical) ( 12 , 19 , 20 , 35 , 39 ) , HT-29 (intestinal) [IKKB (human)] ( 37 ) , HT-29 (intestinal) [Nik (human)] ( 37 ) , hTERT-HME1 ( 3 ) , HUVEC (endothelial) ( 14 ) , Ishikawa (endometrial) ( 26 ) , Jurkat (T lymphocyte) ( 31 , 35 ) , KB (squamous) ( 15 ) , L929 (fibroblast) ( 24 ) , lung ( 25 ) , MEF (fibroblast) [IGF1R (mouse)] ( 29 ) , MT-2 ( 35 ) , NCI-H1299 (pulmonary) ( 22 ) , OCI-ly10 (B lymphocyte) ( 2 ) , OCI-ly3 (B lymphocyte) ( 2 ) , PC3 (prostate cell) ( 28 ) , skin ( 1 ) , SU-DHL-4 (B lymphocyte) ( 2 ) , U2OS (bone cell) ( 12 )

Upstream Regulation
Regulatory protein:
Akt1 (human) ( 5 ) , EGFR (human) ( 3 ) , HSP27 (human) ( 19 ) , IKKB (human) ( 30 ) , LYN (human) ( 3 ) , MAPKAPK2 (human) ( 19 ) , MEKK3 (human) ( 17 ) , PPP2CA (human) ( 15 , 16 ) , SGK1 (human) ( 30 ) , Src (human) ( 15 )
Putative in vivo kinases:
AMPKA2 (human) ( 14 ) , Nik (human) ( 37 )
Kinases, in vitro:
AMPKA2 (human) ( 14 ) , PKCA (human) ( 38 ) , PKCZ (human) ( 38 ) , SGK1 (human) ( 30 )
Putative upstream phosphatases:
PPM1B (human) ( 20 ) , PPPM1A (human) ( 20 )
Treatments:
Akt-I-1 ( 15 ) , anti-CD28 ( 31 ) , anti-CD3 ( 31 ) , bortezomib ( 26 ) , calyculin_A ( 15 ) , CCL5 ( 18 ) , DTT ( 24 ) , EGF ( 3 ) , herbimycin_A ( 15 ) , IGF-1 ( 30 ) , IL-1b ( 15 , 19 , 37 ) , ionomycin ( 16 ) , LBH-589 ( 11 ) , LPA ( 16 ) , LPS ( 3 ) , LY294002 ( 15 ) , MG132 ( 15 ) , PAR1-activating_peptide ( 25 ) , PAR3-activating_peptide ( 25 ) , PAR4-activating_peptide ( 25 ) , PD98059 ( 15 ) , PEITC ( 28 ) , phorbol_ester ( 16 , 33 ) , PIP3 ( 5 ) , salicylate ( 33 ) , SB202190 ( 19 ) , SB203580 ( 24 ) , SC-514 ( 29 ) , seliciclib ( 22 ) , siRNA ( 19 ) , SP600125 ( 15 , 24 , 33 ) , sulforaphane ( 28 ) , TAK1_inhibitor ( 4 ) , thrombin ( 25 ) , TNF ( 19 , 20 , 22 , 24 , 33 , 37 ) , U0126 ( 24 ) , UV ( 28 ) , UVB ( 1 ) , vanadate ( 15 ) , vorinostat ( 11 ) , withaferin_A ( 24 )

Downstream Regulation
Effects of modification on IKKB:
activity, induced ( 18 ) , enzymatic activity, induced ( 7 , 19 , 20 , 35 , 37 , 39 ) , intracellular localization ( 39 ) , molecular association, regulation ( 39 ) , protein stabilization ( 24 )
Effects of modification on biological processes:
cell motility, altered ( 18 ) , transcription, altered ( 24 ) , transcription, induced ( 20 )
Induce interaction with:
IKKA (human) ( 39 )

References 

1

Choi YJ, et al. (2016) The underlying mechanism of proinflammatory NF-κB activation by the mTORC2/Akt/IKKα pathway during skin aging. Oncotarget 7, 52685-52694
27486771   Curated Info

2

Agarwal NK, et al. (2016) Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma. Blood 127, 605-15
26603838   Curated Info

3

De S, et al. (2015) Erlotinib protects against LPS-induced Endotoxicity because TLR4 needs EGFR to signal. Proc Natl Acad Sci U S A 112, 9680-5
26195767   Curated Info

4

Huang HL, Chiang CH, Hung WC, Hou MF (2015) Targeting of TGF-β-activated protein kinase 1 inhibits chemokine (C-C motif) receptor 7 expression, tumor growth and metastasis in breast cancer. Oncotarget 6, 995-1007
25557171   Curated Info

5

Ho MY, Liang CM, Liang SM (2015) MIG-7 and phosphorylated prohibitin coordinately regulate lung cancer invasion/metastasis. Oncotarget 6, 381-93
25575814   Curated Info

6

Gallo LH, et al. (2014) Novel Lys63-linked ubiquitination of IKKβ induces STAT3 signaling. Cell Cycle 13, 3964-76
25486864   Curated Info

7

Shinohara H, et al. (2014) Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation. Science 344, 760-4
24833394   Curated Info

8

Magliozzi R, et al. (2013) Control of Epithelial Cell Migration and Invasion by the IKKβ- and CK1α-Mediated Degradation of RAPGEF2. Dev Cell 27, 574-85
24290981   Curated Info

9

Meyer AN, et al. (2013) Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ. PLoS One 8, e84497
24386391   Curated Info

10

Yang W, et al. (2012) EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell 48, 771-84
23123196   Curated Info

11

Dai Y, et al. (2011) Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors. J Biol Chem 286, 34036-50
21816815   Curated Info

12

Malik SA, et al. (2011) BH3 mimetics activate multiple pro-autophagic pathways. Oncogene 30, 3918-29
21460857   Curated Info

13

Frischbutter S, et al. (2011) Dephosphorylation of Bcl-10 by calcineurin is essential for canonical NF-κB activation in Th cells. Eur J Immunol 41, 2349-57
21674474   Curated Info

14

Bess E, Fisslthaler B, Frömel T, Fleming I (2011) Nitric oxide-induced activation of the AMP-activated protein kinase α2 subunit attenuates IκB kinase activity and inflammatory responses in endothelial cells. PLoS One 6, e20848
21673972   Curated Info

15

Barisic S, Schmidt C, Walczak H, Kulms D (2010) Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFkappaB activation via Src-dependent blockade of PP2A. Biochem Pharmacol 80, 439-47
20450893   Curated Info

16

Sun W, et al. (2010) Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IkappaB kinase beta/nuclear factor-kappaB activation. J Biol Chem 285, 21341-8
20448038   Curated Info

17

Sun W, et al. (2010) Phosphorylation of Thr-516 and Ser-520 in the kinase activation loop of MEKK3 is required for lysophosphatidic acid-mediated optimal IkappaB kinase beta (IKKbeta)/nuclear factor-kappaB (NF-kappaB) activation. J Biol Chem 285, 7911-8
20068038   Curated Info

18

Huang CY, et al. (2009) CCL5 increases lung cancer migration via PI3K, Akt and NF-kappaB pathways. Biochem Pharmacol 77, 794-803
19073147   Curated Info

19

Wu Y, et al. (2009) HSP27 regulates IL-1 stimulated IKK activation through interacting with TRAF6 and affecting its ubiquitination. Cell Signal 21, 143-50
18950704   Curated Info

20

Sun W, et al. (2009) PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation. Cell Signal 21, 95-102
18930133   Curated Info

21

Chen RA, et al. (2008) Inhibition of IkappaB kinase by vaccinia virus virulence factor B14. PLoS Pathog 4, e22
18266467   Curated Info

22

Dey A, et al. (2008) R-Roscovitine simultaneously targets both the p53 and NF-kappaB pathways and causes potentiation of apoptosis: implications in cancer therapy. Cell Death Differ 15, 263-73
17975552   Curated Info

23

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

24

Kaileh M, et al. (2007) Withaferin A strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity. J Biol Chem 282, 4253-64
17150968   Curated Info

25

Lin CH, et al. (2006) c-Src mediates thrombin-induced NF-kappaB activation and IL-8/CXCL8 expression in lung epithelial cells. J Immunol 177, 3427-38
16920985   Curated Info

26

Dolcet X, et al. (2006) Proteasome inhibitors induce death but activate NF-kappaB on endometrial carcinoma cell lines and primary culture explants. J Biol Chem 281, 22118-30
16735506   Curated Info

27

Carter RS, et al. (2005) Site-specific monoubiquitination of IkappaB kinase IKKbeta regulates its phosphorylation and persistent activation. J Biol Chem 280, 43272-9
16267042   Curated Info

28

Xu C, et al. (2005) Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24, 4486-95
15856023   Curated Info

29

Jeong SJ, et al. (2005) A novel NF-kappaB pathway involving IKKbeta and p65/RelA Ser-536 phosphorylation results in p53 Inhibition in the absence of NF-kappaB transcriptional activity. J Biol Chem 280, 10326-32
15611068   Curated Info

30

Zhang L, Cui R, Cheng X, Du J (2005) Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating I{kappa}B kinase. Cancer Res 65, 457-64
15695387   Curated Info

31

Mattioli I, et al. (2004) Transient and selective NF-kappa B p65 serine 536 phosphorylation induced by T cell costimulation is mediated by I kappa B kinase beta and controls the kinetics of p65 nuclear import. J Immunol 172, 6336-44
15128824   Curated Info

32

Carter RS, et al. (2003) Signal-induced ubiquitination of I kappaB Kinase-beta. J Biol Chem 278, 48903-6
14514672   Curated Info

33

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

34

Wang C, et al. (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346-51
11460167   Curated Info

35

Carter RS, et al. (2001) Persistent activation of NF-kappa B by the tax transforming protein involves chronic phosphorylation of IkappaB kinase subunits IKKbeta and IKKgamma. J Biol Chem 276, 24445-8
11325957   Curated Info

36

Huynh QK, et al. (2000) Characterization of the recombinant IKK1/IKK2 heterodimer. Mechanisms regulating kinase activity. J Biol Chem 275, 25883-91
10823818   Curated Info

37

Delhase M, Hayakawa M, Chen Y, Karin M (1999) Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 284, 309-13
10195894   Curated Info

38

Lallena MJ, et al. (1999) Activation of IkappaB kinase beta by protein kinase C isoforms. Mol Cell Biol 19, 2180-8
10022904   Curated Info

39

Mercurio F, et al. (1997) IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 278, 860-6
9346484   Curated Info