Thr261
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Home > Phosphorylation Site Page: > Thr261  -  MKK4 (human)

Site Information
LVDsIAKtRDAGCRP   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447656

In vivo Characterization
Methods used to characterize site in vivo:
electrophoretic mobility shift ( 14 ) , mass spectrometry ( 1 , 5 , 6 ) , mutation of modification site ( 20 ) , phospho-antibody ( 2 , 3 , 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ) , western blotting ( 2 , 3 , 4 , 7 , 8 , 13 , 18 )
Disease tissue studied:
luminal A breast cancer ( 1 ) , leukemia ( 3 ) , T cell leukemia ( 3 ) , liver cancer ( 18 ) , lung cancer ( 8 , 14 ) , neuroblastoma ( 2 ) , oropharyngeal cancer ( 8 ) , squamous cell carcinoma of the oropharynx ( 8 ) , pancreatic cancer ( 7 ) , pancreatic carcinoma ( 7 ) , prostate cancer ( 4 )
Relevant cell line - cell type - tissue:
293 (epithelial) [MKK4 (human)] ( 17 ) , 293 (epithelial) [MLK3 (human)] ( 17 ) , A549 (pulmonary) ( 8 , 14 ) , breast ( 1 ) , Detroit562 (squamous) ( 8 ) , DU 145 (prostate cell) ( 11 ) , fibroblast-foreskin [HRas (human)] ( 15 ) , HeLa (cervical) ( 4 , 20 ) , HepG2 (hepatic) ( 16 , 18 ) , Jurkat (T lymphocyte) ( 3 , 6 ) , LNCaP (prostate cell) ( 4 ) , mesangial ( 13 ) , MM (B lymphocyte) ( 12 ) , ovary ( 9 ) , PANC-1 (pancreatic) [PRKD1 (human), transfection] ( 7 ) , PREC (epithelial) ( 10 ) , SH-SY5Y (neural crest) ( 2 )

Upstream Regulation
Regulatory protein:
Akt1 (human) ( 2 ) , DUSP14 (human) ( 3 ) , JIP3 (human) ( 11 ) , PRKD1 (human) ( 7 )
Putative in vivo kinases:
ASK1 (human) ( 11 ) , MLK3 (human) ( 17 , 20 )
Kinases, in vitro:
MKK4 (human) ( 19 ) , MLK3 (human) ( 20 )
Putative upstream phosphatases:
PPP5C (human) ( 14 )
Treatments:
angiopoietin-1 ( 10 ) , anisomycin ( 2 ) , anti-CD3 ( 3 ) , bortezomib ( 12 ) , CCT007093 ( 4 ) , CTGF ( 13 ) , glucose_starvation ( 11 ) , H2O2 ( 10 ) , hypoxia ( 14 ) , IL-6 ( 16 , 18 ) , ionizing_radiation ( 4 ) , LY294002 ( 10 ) , neurotensin ( 7 ) , pneumolysin ( 8 ) , rottlerin ( 16 ) , siRNA ( 14 ) , vanadate ( 8 ) , wortmannin ( 10 )

Downstream Regulation
Effects of modification on MKK4:
enzymatic activity, induced ( 14 , 18 , 19 )
Effects of modification on biological processes:
transcription, induced ( 18 )

References 

1

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

2

Fey D, et al. (2015) Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients. Sci Signal 8, ra130
26696630   Curated Info

3

Yang CY, et al. (2014) Dual-Specificity Phosphatase 14 (DUSP14/MKP6) Negatively Regulates TCR Signaling by Inhibiting TAB1 Activation. J Immunol 192, 1547-57
24403530   Curated Info

4

Song JY, et al. (2013) Wip1 suppresses apoptotic cell death through direct dephosphorylation of BAX in response to γ-radiation. Cell Death Dis 4, e744
23907458   Curated Info

5

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

6

Mulhern D (2012) CST Curation Set: 13112; Year: 2012; Biosample/Treatment: cell line, Jurkat/calyculin_A & pervanadate; Disease: T cell leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY])
Curated Info

7

Kisfalvi K, Hurd C, Guha S, Rozengurt E (2010) Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells. J Cell Physiol 223, 309-16
20082306   Curated Info

8

Aguilar JL, et al. (2009) Phosphatase-dependent regulation of epithelial mitogen-activated protein kinase responses to toxin-induced membrane pores. PLoS One 4, e8076
19956644   Curated Info

9

Spillman MA, et al. (2007) Regulation of the metastasis suppressor gene MKK4 in ovarian cancer. Gynecol Oncol 105, 312-20
17276500   Curated Info

10

Murakami T, et al. (2005) Angiopoietin-1 attenuates H2O2-induced SEK1/JNK phosphorylation through the phosphatidylinositol 3-kinase/Akt pathway in vascular endothelial cells. J Biol Chem 280, 31841-9
16000309   Curated Info

11

Song JJ, Lee YJ (2005) Cross-talk between JIP3 and JIP1 during glucose deprivation: SEK1-JNK2 and Akt1 act as mediators. J Biol Chem 280, 26845-55
15911620   Curated Info

12

Hideshima T, et al. (2005) Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. Oncogene 24, 3121-9
15735676   Curated Info

13

Wahab NA, Weston BS, Mason RM (2005) Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA. J Am Soc Nephrol 16, 340-51
15601748   Curated Info

14

Zhou G, Golden T, Aragon IV, Honkanen RE (2004) Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. J Biol Chem 279, 46595-605
15328343   Curated Info

15

Wang W, et al. (2002) Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol 22, 3389-403
11971971   Curated Info

16

Schuringa JJ, Dekker LV, Vellenga E, Kruijer W (2001) Sequential activation of Rac-1, SEK-1/MKK-4, and protein kinase Cdelta is required for interleukin-6-induced STAT3 Ser-727 phosphorylation and transactivation. J Biol Chem 276, 27709-15
11335711   Curated Info

17

Leung IW, Lassam N (2001) The kinase activation loop is the key to mixed lineage kinase-3 activation via both autophosphorylation and hematopoietic progenitor kinase 1 phosphorylation. J Biol Chem 276, 1961-7
11053428   Curated Info

18

Schuringa JJ, et al. (2000) Interleukin-6-induced STAT3 transactivation and Ser727 phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components. Biochem J 347 Pt 1, 89-96
10727406   Curated Info

19

Deacon K, Blank JL (1997) Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. J Biol Chem 272, 14489-96
9162092   Curated Info

20

Tibbles LA, et al. (1996) MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. EMBO J 15, 7026-35
9003778   Curated Info