Protein-coding gene in the species Homo sapiens
Mitogen-Activated Protein Kinase Kinase Kinase 2 also known as MEKK2 (MEK/ERK Kinase 2) is anenzyme that in humans is encoded by theMAP3K2 gene .[ 5] [ 6] [ 7]
The protein encoded by this gene is a member ofserine/threonine protein kinase family. Thiskinase preferentially activates other kinases involved in theMAP kinase signaling pathway . This kinase has been shown to directly phosphorylate and activateIkappaB kinases , and thus plays a role inNF-kappa B signaling pathway. This kinase has also been found to bind and activateprotein kinase C -related kinase 2 , which suggests its involvement in a regulated signaling process.[ 7]
MEKK2 is activated through homodimerization and subsequent trans-autophosphorylation at MEKK2-S519.[ 8] [ 9]
MEKK2 is regulated by14-3-3 proteins which bind to MEKK2-phosphoT283.[ 10]
MEKK2 is regulated by SMYD3 which binds and methylates MEKK2-K260.[ 11]
MAP3K2 has been shown tointeract with:
^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 . 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
