Protein-coding gene in the species Homo sapiens
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
^ a b c GRCh38: Ensembl release 89: ENSG00000169967 – Ensembl , May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024383 – Ensembl , May 2017^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ 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 . ^ 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 . ^ a b "Entrez Gene: MAP3K2 mitogen-activated protein kinase kinase kinase 2" .^ 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 . ^ 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 . ^ 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 . ^ a b 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 . ^ 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– 2342. doi :10.1128/mcb.20.7.2334-2342.2000 . PMC 85399 PMID 10713157 . ^ 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 . ^ a b 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 . ^ 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 . ^ 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 .
PDB gallery
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)
Activity Regulation Classification Kinetics Types
