MAP3K2

Protein-coding gene in the species Homo sapiens
MAP3K2
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

2CU1, 2NPT, 5EX0, 5HQ8

Identifiers
AliasesMAP3K2, MEKK2, MEKK2B, mitogen-activated protein kinase kinase kinase 2
External IDsOMIM: 609487; MGI: 1346873; HomoloGene: 74576; GeneCards: MAP3K2; OMA:MAP3K2 - orthologs
Gene location (Human)
Chromosome 2 (human)
Chr.Chromosome 2 (human)[1]
Chromosome 2 (human)
Genomic location for MAP3K2
Genomic location for MAP3K2
Band2q14.3Start127,298,668 bp[1]
End127,388,465 bp[1]
Gene location (Mouse)
Chromosome 18 (mouse)
Chr.Chromosome 18 (mouse)[2]
Chromosome 18 (mouse)
Genomic location for MAP3K2
Genomic location for MAP3K2
Band18|18 B1Start32,296,142 bp[2]
End32,369,804 bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • jejunal mucosa

  • trabecular bone

  • caput epididymis

  • corpus epididymis

  • nipple

  • bronchial epithelial cell

  • pylorus

  • lower lobe of lung

  • saphenous vein

  • vulva
Top expressed in
  • renal corpuscle

  • medullary collecting duct

  • ciliary body

  • iris

  • substantia nigra

  • Paneth cell

  • cumulus cell

  • fossa

  • conjunctival fornix

  • condyle
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
  • nucleotide binding
  • protein binding
  • protein kinase binding
  • kinase activity
  • ATP binding
  • protein serine/threonine kinase activity
  • transferase activity
  • MAP kinase kinase kinase activity
  • metal ion binding
  • protein kinase activity
Cellular component
  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol
Biological process
  • phosphorylation
  • positive regulation of transcription, DNA-templated
  • cellular response to mechanical stimulus
  • protein phosphorylation
  • regulation of mitotic cell cycle
  • regulation of apoptotic process
  • signal transduction
  • stress-activated protein kinase signaling cascade
  • activation of protein kinase activity
Sources:Amigo / QuickGO
Orthologs
SpeciesHumanMouse
Entrez

10746

26405

Ensembl

ENSG00000169967

ENSMUSG00000024383

UniProt

Q9Y2U5

Q61083

RefSeq (mRNA)

NM_006609
NM_001371910
NM_001371911

NM_011946

RefSeq (protein)

NP_006600
NP_001358839
NP_001358840

NP_036076

Location (UCSC)Chr 2: 127.3 – 127.39 MbChr 18: 32.3 – 32.37 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mitogen-Activated Protein Kinase Kinase Kinase 2 also known as MEKK2 (MEK/ERK Kinase 2) is an enzyme that in humans is encoded by the MAP3K2 gene.[5][6][7]

Function

The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase preferentially activates other kinases involved in the MAP kinase signaling pathway. This kinase has been shown to directly phosphorylate and activate IkappaB kinases, and thus plays a role in NF-kappa B signaling pathway. This kinase has also been found to bind and activate protein kinase C-related kinase 2, which suggests its involvement in a regulated signaling process.[7]

Activation

MEKK2 is activated through homodimerization and subsequent trans-autophosphorylation at MEKK2-S519.[8][9]

MEKK2 is regulated by 14-3-3 proteins which bind to MEKK2-phosphoT283.[10]

MEKK2 is regulated by SMYD3 which binds and methylates MEKK2-K260.[11]

Interactions

MAP3K2 has been shown to interact with:

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000169967 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024383 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Blank JL, Gerwins P, Elliott EM, Sather S, Johnson GL (Mar 1996). "Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase". The Journal of Biological Chemistry. 271 (10): 5361–8. doi:10.1074/jbc.271.10.5361. PMID 8621389.
  6. ^ Zhao Q, Lee FS (Mar 1999). "Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta". The Journal of Biological Chemistry. 274 (13): 8355–8. doi:10.1074/jbc.274.13.8355. PMID 10085062.
  7. ^ a b "Entrez Gene: MAP3K2 mitogen-activated protein kinase kinase kinase 2".
  8. ^ Cheng J, Yu L, Zhang D, Huang Q, Spencer D, Su B (2005-04-08). "Dimerization through the Catalytic Domain Is Essential for MEKK2 Activation". Journal of Biological Chemistry. 280 (14): 13477–13482. doi:10.1074/jbc.M414258200. ISSN 0021-9258. PMID 15695508.
  9. ^ Zhang D, Facchinetti V, Wang X, Huang Q, Qin J, Su B (2006-01-11). "Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways". The EMBO Journal. 25 (1): 97–107. doi:10.1038/sj.emboj.7600913. ISSN 0261-4189. PMC 1356356. PMID 16362041.
  10. ^ Matitau AE, Gabor TV, Gill RM, Scheid MP (2013-09-27). "MEKK2 kinase association with 14-3-3 protein regulates activation of c-Jun N-terminal kinase". The Journal of Biological Chemistry. 288 (39): 28293–28302. doi:10.1074/jbc.M113.511352. ISSN 1083-351X. PMC 3784737. PMID 23963453.
  11. ^ a b Mazur PK, Reynoird N, Khatri P, Jansen PW, Wilkinson AW, Liu S, Barbash O, Van Aller GS, Huddleston M, Dhanak D, Tummino PJ (June 2014). "SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer". Nature. 510 (7504): 283–287. Bibcode:2014Natur.510..283M. doi:10.1038/nature13320. ISSN 1476-4687. PMC 4122675. PMID 24847881.
  12. ^ a b Cheng J, Yang J, Xia Y, Karin M, Su B (Apr 2000). "Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation". Molecular and Cellular Biology. 20 (7): 2334–42. doi:10.1128/mcb.20.7.2334-2342.2000. PMC 85399. PMID 10713157.
  13. ^ Deacon K, Blank JL (1997-05-30). "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". The Journal of Biological Chemistry. 272 (22): 14489–14496. doi:10.1074/jbc.272.22.14489. ISSN 0021-9258. PMID 9162092.
  14. ^ a b Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry. 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
  15. ^ Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR (1998-02-06). "14-3-3 Proteins Interact with Specific MEK Kinases". Journal of Biological Chemistry. 273 (6): 3476–3483. doi:10.1074/jbc.273.6.3476. ISSN 0021-9258. PMID 9452471.
  16. ^ Winsauer G, Resch U, Hofer-Warbinek R, Schichl YM, de Martin R (Nov 2008). "XIAP regulates bi-phasic NF-kappaB induction involving physical interaction and ubiquitination of MEKK2". Cellular Signalling. 20 (11): 2107–12. doi:10.1016/j.cellsig.2008.08.004. PMID 18761086.

Further reading

  • Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ (1995). "Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1". Nature. 372 (6508): 798–800. doi:10.1038/372798a0. PMID 7997270. S2CID 4369739.
  • Wu Z, Wu J, Jacinto E, Karin M (Dec 1997). "Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase". Molecular and Cellular Biology. 17 (12): 7407–16. doi:10.1128/mcb.17.12.7407. PMC 232596. PMID 9372971.
  • Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR (Feb 1998). "14-3-3 proteins interact with specific MEK kinases". The Journal of Biological Chemistry. 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. PMID 9452471.
  • Cheng J, Yang J, Xia Y, Karin M, Su B (Apr 2000). "Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation". Molecular and Cellular Biology. 20 (7): 2334–42. doi:10.1128/MCB.20.7.2334-2342.2000. PMC 85399. PMID 10713157.
  • Sun W, Vincent S, Settleman J, Johnson GL (Aug 2000). "MEK kinase 2 binds and activates protein kinase C-related kinase 2. Bifurcation of kinase regulatory pathways at the level of an MAPK kinase kinase". The Journal of Biological Chemistry. 275 (32): 24421–8. doi:10.1074/jbc.M003148200. PMID 10818102.
  • Garrington TP, Ishizuka T, Papst PJ, Chayama K, Webb S, Yujiri T, Sun W, Sather S, Russell DM, Gibson SB, Keller G, Gelfand EW, Johnson GL (Oct 2000). "MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells". The EMBO Journal. 19 (20): 5387–95. doi:10.1093/emboj/19.20.5387. PMC 314024. PMID 11032806.
  • Huang J, Tu Z, Lee FS (Apr 2003). "Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity". Biochemical and Biophysical Research Communications. 303 (2): 532–40. doi:10.1016/S0006-291X(03)00387-5. PMID 12659851.
  • Nakamura K, Johnson GL (Sep 2003). "PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway". The Journal of Biological Chemistry. 278 (39): 36989–92. doi:10.1074/jbc.C300313200. PMID 12912994.
  • Hammaker DR, Boyle DL, Chabaud-Riou M, Firestein GS (Feb 2004). "Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis". Journal of Immunology. 172 (3): 1612–8. doi:10.4049/jimmunol.172.3.1612. PMID 14734742.
  • Raviv Z, Kalie E, Seger R (Apr 2004). "MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation". Journal of Cell Science. 117 (Pt 9): 1773–84. doi:10.1242/jcs.01040. PMID 15075238.
  • Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T (Aug 2004). "Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization". Current Biology. 14 (16): 1436–50. Bibcode:2004CBio...14.1436J. doi:10.1016/j.cub.2004.07.051. PMID 15324660. S2CID 2371325.
  • Benzinger A, Muster N, Koch HB, Yates JR, Hermeking H (Jun 2005). "Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer". Molecular & Cellular Proteomics. 4 (6): 785–95. doi:10.1074/mcp.M500021-MCP200. PMID 15778465.
  • Cheng J, Zhang D, Kim K, Zhao Y, Zhao Y, Su B (Jul 2005). "Mip1, an MEKK2-interacting protein, controls MEKK2 dimerization and activation". Molecular and Cellular Biology. 25 (14): 5955–64. doi:10.1128/MCB.25.14.5955-5964.2005. PMC 1168836. PMID 15988011.
  • Pelkmans L, Zerial M (Jul 2005). "Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae". Nature. 436 (7047): 128–33. Bibcode:2005Natur.436..128P. doi:10.1038/nature03866. PMID 16001074. S2CID 4309375.
  • Wissing J, Jänsch L, Nimtz M, Dieterich G, Hornberger R, Kéri G, Wehland J, Daub H (Mar 2007). "Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry". Molecular & Cellular Proteomics. 6 (3): 537–47. doi:10.1074/mcp.T600062-MCP200. hdl:10033/19756. PMID 17192257.
  • v
  • t
  • e
  • 2cu1: Solution structure of the PB1 domain of human protein kinase MEKK2b
    2cu1: Solution structure of the PB1 domain of human protein kinase MEKK2b
  • 2npt: Crystal Structure of the complex of human mitogen activated protein kinase kinase 5 phox domain (MAP2K5-phox) with human mitogen activated protein kinase kinase kinase 2 phox domain (MAP3K2-phox)
    2npt: Crystal Structure of the complex of human mitogen activated protein kinase kinase 5 phox domain (MAP2K5-phox) with human mitogen activated protein kinase kinase kinase 2 phox domain (MAP3K2-phox)
  • v
  • t
  • e
Non-specific serine/threonine protein kinases (EC 2.7.11.1)
Pyruvate dehydrogenase kinase (EC 2.7.11.2)
Dephospho-(reductase kinase) kinase (EC 2.7.11.3)
3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring) kinase (EC 2.7.11.4)
(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)
(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)
Myosin-heavy-chain kinase (EC 2.7.11.7)
Fas-activated serine/threonine kinase (EC 2.7.11.8)
Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)
  • -
IκB kinase (EC 2.7.11.10)
cAMP-dependent protein kinase (EC 2.7.11.11)
cGMP-dependent protein kinase (EC 2.7.11.12)
Protein kinase C (EC 2.7.11.13)
Rhodopsin kinase (EC 2.7.11.14)
Beta adrenergic receptor kinase (EC 2.7.11.15)
G-protein coupled receptor kinases (EC 2.7.11.16)
Ca2+/calmodulin-dependent (EC 2.7.11.17)
Myosin light-chain kinase (EC 2.7.11.18)
Phosphorylase kinase (EC 2.7.11.19)
Elongation factor 2 kinase (EC 2.7.11.20)
Polo kinase (EC 2.7.11.21)
Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)
Polo kinase (EC 2.7.11.21)
Cyclin-dependent kinase (EC 2.7.11.22)
(RNA-polymerase)-subunit kinase (EC 2.7.11.23)
Mitogen-activated protein kinase (EC 2.7.11.24)
MAP3K (EC 2.7.11.25)
Tau-protein kinase (EC 2.7.11.26)
(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)
  • -
Tropomyosin kinase (EC 2.7.11.28)
  • -
Low-density-lipoprotein receptor kinase (EC 2.7.11.29)
  • -
Receptor protein serine/threonine kinase (EC 2.7.11.30)
MAP2K
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