MAP3K2 explained

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.^{[1] [2] [3]}

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.

Activation

MEKK2 is activated through homodimerization and subsequent trans-autophosphorylation at MEKK2-S519.^{[4] [5]}

MEKK2 is regulated by 14-3-3 proteins which bind to MEKK2-phosphoT283.^[6]

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

Interactions

MAP3K2 has been shown to interact with:

• MAPK8,
• MAP2K4,^[7]
• MAP2K5,
• MAP2K7,^[8]
• 14-3-3 protein,^[9]
• SMYD3,^[10]
• SH2D2A,^[11] and
• XIAP^[12]

Further reading

• Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ . Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 . Nature . 372 . 6508 . 798–800 . 1995 . 7997270 . 10.1038/372798a0 . 4369739 .
• Wu Z, Wu J, Jacinto E, Karin M . Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase . Molecular and Cellular Biology . 17 . 12 . 7407–16 . Dec 1997 . 9372971 . 232596 . 10.1128/mcb.17.12.7407.
• Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR . 14-3-3 proteins interact with specific MEK kinases . The Journal of Biological Chemistry . 273 . 6 . 3476–83 . Feb 1998 . 9452471 . 10.1074/jbc.273.6.3476 . free .
• Cheng J, Yang J, Xia Y, Karin M, Su B . 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 . Apr 2000 . 10713157 . 85399 . 10.1128/MCB.20.7.2334-2342.2000 .
• Sun W, Vincent S, Settleman J, Johnson GL . 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 . Aug 2000 . 10818102 . 10.1074/jbc.M003148200 . free .
• 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 . 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 . Oct 2000 . 11032806 . 314024 . 10.1093/emboj/19.20.5387 .
• Huang J, Tu Z, Lee FS . Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity . Biochemical and Biophysical Research Communications . 303 . 2 . 532–40 . Apr 2003 . 12659851 . 10.1016/S0006-291X(03)00387-5 .
• Nakamura K, Johnson GL . 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 . Sep 2003 . 12912994 . 10.1074/jbc.C300313200 . free .
• Hammaker DR, Boyle DL, Chabaud-Riou M, Firestein GS . 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 . Feb 2004 . 14734742 . 10.4049/jimmunol.172.3.1612 . free .
• Raviv Z, Kalie E, Seger R . 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 . Apr 2004 . 15075238 . 10.1242/jcs.01040 . free .
• 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 . 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 . Aug 2004 . 15324660 . 10.1016/j.cub.2004.07.051 . 2371325 . free . 2004CBio...14.1436J .
• Benzinger A, Muster N, Koch HB, Yates JR, Hermeking H . Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer . Molecular & Cellular Proteomics . 4 . 6 . 785–95 . Jun 2005 . 15778465 . 10.1074/mcp.M500021-MCP200 . free .
• Cheng J, Zhang D, Kim K, Zhao Y, Zhao Y, Su B . Mip1, an MEKK2-interacting protein, controls MEKK2 dimerization and activation . Molecular and Cellular Biology . 25 . 14 . 5955–64 . Jul 2005 . 15988011 . 1168836 . 10.1128/MCB.25.14.5955-5964.2005 .
• Pelkmans L, Zerial M . Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae . Nature . 436 . 7047 . 128–33 . Jul 2005 . 16001074 . 10.1038/nature03866 . 2005Natur.436..128P . 4309375 .
• Wissing J, Jänsch L, Nimtz M, Dieterich G, Hornberger R, Kéri G, Wehland J, Daub H . Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry . Molecular & Cellular Proteomics . 6 . 3 . 537–47 . Mar 2007 . 17192257 . 10.1074/mcp.T600062-MCP200 . free . 10033/19756 . free .

Notes and References

1. Blank JL, Gerwins P, Elliott EM, Sather S, Johnson GL . 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 . Mar 1996 . 8621389 . 10.1074/jbc.271.10.5361 . free .
2. Zhao Q, Lee FS . 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 . Mar 1999 . 10085062 . 10.1074/jbc.274.13.8355 . free .
3. Web site: Entrez Gene: MAP3K2 mitogen-activated protein kinase kinase kinase 2.
4. 2005-04-08. Dimerization through the Catalytic Domain Is Essential for MEKK2 Activation. Journal of Biological Chemistry. en. 280. 14. 13477–13482. 10.1074/jbc.M414258200. 0021-9258. free. Cheng. Jinke. Yu. Ling. Zhang. Dongyu. Huang. Qiaojia. Spencer. David. Su. Bing. 15695508.
5. Zhang. Dongyu. Facchinetti. Valeria. Wang. Xiaofang. Huang. Qiaojia. Qin. Jun. Su. Bing. 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. 10.1038/sj.emboj.7600913. 0261-4189. 1356356. 16362041.
6. Matitau. Adi E.. Gabor. Timothy V.. Gill. R. Montgomery. Scheid. Michael P.. 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. 10.1074/jbc.M113.511352. 1083-351X. 3784737. 23963453. free .
7. Deacon. K.. Blank. J. L.. 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. 10.1074/jbc.272.22.14489. 0021-9258. 9162092. free.
8. Cheng J, Yang J, Xia Y, Karin M, Su B . 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 . Apr 2000 . 10713157 . 85399 . 10.1128/mcb.20.7.2334-2342.2000.
9. 1998-02-06. 14-3-3 Proteins Interact with Specific MEK Kinases. Journal of Biological Chemistry. en. 273. 6. 3476–3483. 10.1074/jbc.273.6.3476. 0021-9258. free. Fanger. Gary R.. Widmann. Christian. Porter. Amy C.. Sather. Sue. Johnson. Gary L.. Vaillancourt. Richard R.. 9452471.
10. Mazur. Pawel K.. Reynoird. Nicolas. Khatri. Purvesh. Jansen. Pascal W. T. C.. Wilkinson. Alex W.. Liu. Shichong. Barbash. Olena. Van Aller. Glenn S.. Huddleston. Michael. Dhanak. Dashyant. Tummino. Peter J.. June 2014. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature. en. 510. 7504. 283–287. 10.1038/nature13320. 24847881. 1476-4687. 4122675. 2014Natur.510..283M.
11. Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL . MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway . The Journal of Biological Chemistry . 276 . 7 . 5093–100 . Feb 2001 . 11073940 . 10.1074/jbc.M003719200 . free .
12. Winsauer G, Resch U, Hofer-Warbinek R, Schichl YM, de Martin R . XIAP regulates bi-phasic NF-kappaB induction involving physical interaction and ubiquitination of MEKK2 . Cellular Signalling . 20 . 11 . 2107–12 . Nov 2008 . 18761086 . 10.1016/j.cellsig.2008.08.004 . free .