MAP3K2

MAP3K2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CU1, 2NPT, 5EX0, 5HQ8
Identifiers
Aliases	MAP3K2 , MEKK2, MEKK2B, mitogen-activated protein kinase kinase kinase 2
External IDs	OMIM: 609487; MGI: 1346873; HomoloGene: 74576; GeneCards: MAP3K2; OMA:MAP3K2 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q14.3 Start 127,298,668 bp [1] End 127,388,465 bp [1]
Gene location (Mouse) Chr. Chromosome 18 (mouse) [2] Band 18|18 B1 Start 32,296,142 bp [2] End 32,369,804 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in jejunal mucosa mucosa of paranasal sinus trabecular bone tail of epididymis caput epididymis corpus epididymis epithelium of nasopharynx nipple bronchial epithelial cell pylorus Top expressed in Rostral migratory stream renal corpuscle medullary collecting duct ciliary body iris substantia nigra Paneth cell cumulus cell fossa conjunctival fornix 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 Species Human Mouse 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 Mb Chr 18: 32.3 – 32.37 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/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:

• MAPK8, ^[12]
• MAP2K4, ^[13]
• MAP2K5, ^[14]
• MAP2K7, ^[12]
• 14-3-3 protein, ^[15]
• SMYD3, ^[11]
• SH2D2A, ^[14] and
• XIAP ^[16]

References

1. GRCh38: Ensembl release 89: ENSG00000169967 – Ensembl, May 2017
2. 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): 5361–5368. 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): 8355–8358. doi: 10.1074/jbc.274.13.8355 . PMID   10085062.
7. "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". The 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. Mazur PK, Reynoird N, Khatri P, Jansen PW, Wilkinson AW, Liu S, et al. (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. 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): 2334–2342. 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. Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, et al. (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry. 276 (7): 5093–5100. 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". The 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): 2107–2112. doi: 10.1016/j.cellsig.2008.08.004 . PMID   18761086.

Further reading

• Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, et al. (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): 7407–7416. 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): 3476–3483. 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): 2334–2342. 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): 24421–24428. doi: 10.1074/jbc.M003148200 . PMID   10818102.
• Garrington TP, Ishizuka T, Papst PJ, Chayama K, Webb S, Yujiri T, et al. (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): 5387–5395. 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): 532–540. 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): 36989–36992. 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). Baltimore, Md.: 1612–1618. 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): 1773–1784. doi: 10.1242/jcs.01040 . PMID   15075238.
• Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, et al. (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): 1436–1450. 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): 785–795. 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): 5955–5964. 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): 128–133. Bibcode:2005Natur.436..128P. doi:10.1038/nature03866. PMID   16001074. S2CID   4309375.
• Wissing J, Jänsch L, Nimtz M, Dieterich G, Hornberger R, Kéri G, et al. (Mar 2007). "Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry". Molecular & Cellular Proteomics. 6 (3): 537–547. doi: 10.1074/mcp.T600062-MCP200 . hdl: 10033/19756 . PMID   17192257.