Protein-coding gene in the species Homo sapiens
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal MAP3K1 gene .[ 5] [ 6]
MAP3K1 (or MEKK1) is a serine/threonine kinase and ubiquitin ligase that performs a pivotal role in a network of enzymes integrating cellular receptor responses to a number of mitogenic and metabolic stimuli, including: TNF receptor superfamily (TNFRs), T-cell receptor (TCR), Epidermal growth factor receptor (EGFR), and TGF beta receptor (TGFβR).[ 7] [ 8] Mitogen-activated protein kinase kinases (MAP2Ks) are substrates for direct phosphorylation by the MAP3K1 protein kinase .[ 9] [ 10] The MAP3K1 kinase domain may also be a modest activator of IκB kinase activation.[ 11] The MAP3K1 E3 ubiquitin ligase recruits a ubiquitin-conjugating enzyme (including UBE2D2 , UBE2D3 , and UBE2N :UBE2V1 ) that has been loaded with ubiquitin , interacts with its substrates, and facilitates the transfer of ubiquitin from the ubiquitin-conjugating enzyme onto its substrates.[ 12] Genetics has revealed that MAP3K1 is important in: embryonic development , tumorigenesis , cell growth , cell migration , cytokine production, and humoral immunity .[ 8] MAP3K1 mutants were identified in breast cancer by GWAS .[ 13] [ 14]
MAP3K1 contains a protein kinase domain , PHD finger (which has a RING finger domain -like structure) that serves as an E3 ubiquitin ligase , and scaffold protein regions that mediate protein–protein interactions .[ 15] [ 16] [ 17] [ 18]
Genetic analyses in murine and avian models [ edit ]
MAP3K1 is highly conserved in Euteleostomi .[ 19] The spontaneous recessive lidgap-Gates mutation (deletion of Map3k1 exons 2–9, initially described in the 1960s) identified on the SELH/Bc mouse strain causes the same open-eyelids-at-birth mutational phenotype as the gene knockout mutations of the mouse (but not human) MAP3K1 homolog (Map3k1 ) and also co-maps to distal Chromosome 13.[ 20] MAP3K1 was analysed genetically by targeted mutagenesis using transgenic mice (C57BL/6 and C57BL/6 × 129 backgrounds), embryonic stem cells , and the DT40 cell line to identify genetic traits .
Mechanism of MAPK activation by MAP3K1 [ edit ]
MAP3K1 contains multiple amino acid sites that are phosphorylated and ubiquitinated .[ 33] Early biochemical analysis demonstrated that triple co-expression of MAP3K1, MAP2K and MAPK in bacterial cells was sufficient for the activation of MAPK.[ 34] Later analysis of syngenic mice that harbour mutations in TRAF2 , UBE2N , Map3k1 and Map3k7 identified critical regulators of cytokine-induced MAPK signal transduction in B cells.[ 35] [ 36] [ 37] [ 38] Cytokine signaling through MAP3K1 utilises two-stage cell signaling to recruit the signal transduction mechanism to cytokine receptors and then release the signal transduction components, altered by post-translational modification , from the cellular membrane to activate MAPKs.[ 39] [ 40] Genetic analysis has demonstrated that the E3 Ub ligase and the kinase domains of MAP3K1 are required for MAPK activation.[ 32] [ 41] [ 42]
MAP3K1 signal transduction . A . Cytokine receptor prior to ligation by cytokine. B . Recruitment of TRAFs 2, 3 and 6 to the cytokine receptor. C . Ubiquitination of TRAFs. Recruitment of MAP3K1 and MAP3K7 signaling modules to TRAFs and scaffolding. D . Degradation of canonical Ubiquitin-TRAF3 by the proteasome, release of non-canonical Ubiquitin-TRAF2 and -MAP3Ks into the cytoplasm, and activation of MAP2K signaling.
Cancers, other diseases and therapeutic targeting[ edit ]
MAP3K1 is a biomarker mutated in 3.24% of all human cancers.[ 43] MAP3K1 has been associated with several diseases in non-syngeneic human populations,[ 44] including: breast cancer ,[ 45] adenocarcinoma of the prostate ,[ 46] sarcomatoid hepatocellular carcinoma ,[ 47] acute respiratory distress syndrome ,[ 48] Langerhans cell histiocytosis ,[ 49] and 46,XY disorders of sex development .[ 50] E6201 is an enzyme inhibitor of MAP3K1 that shows cross-specificity with MAP2K1 .[ 51]
Interaction partners [ edit ]
MAP3K1 has been shown to interact with a number of proteins,[ 44] including:
AXIN1 ,[ 52] [ 53]
C-Raf , MAP2K1 , MAPK1 ,[ 54]
Grb2 ,[ 55]
MAPK8 ,[ 56]
TRAF2 ,[ 57]
UBE2I .[ 58]
TAB1 , TNIP1 , TNIP2 . Signal transducing adaptor molecule ,[ 41]
Transforming protein RhoA ,[ 59]
RAC1 , CDC42 ,[ 60]
ARHGAP4 ,[ 61]
MAP2K4 ,[ 62] and
PTK2 .[ 63]
^ a b c GRCh38: Ensembl release 89: ENSG00000095015 – Ensembl , May 2017
^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021754 – 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 .
^ Vinik BS, Kay ES, Fiedorek FT (November 1995). "Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome 5". Mammalian Genome . 6 (11): 782–783. doi :10.1007/BF00539003 . PMID 8597633 . S2CID 37828255 .
^ "Entrez Gene: MAP3K1 mitogen-activated protein kinase kinase kinase 1" .
^ Schlesinger TK, Fanger GR, Yujiri T, Johnson GL (November 1998). "The TAO of MEKK". Frontiers in Bioscience . 3 (4): D1181–D1186. doi :10.2741/a354 . PMID 9820741 .
^ a b Suddason T, Gallagher E (April 2015). "A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1" . Cell Death and Differentiation . 22 (4): 540–548. doi :10.1038/cdd.2014.239 . PMC 4356348 . PMID 25613373 .
^ Minden A, Lin A, McMahon M, Lange-Carter C, Dérijard B, Davis RJ, et al. (December 1994). "Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK". Science . 266 (5191): 1719–1723. Bibcode :1994Sci...266.1719M . doi :10.1126/science.7992057 . PMID 7992057 .
^ Karin M, Gallagher E (2005). "From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance". IUBMB Life . 57 (4–5): 283–295. doi :10.1080/15216540500097111 . PMID 16036612 . S2CID 25508987 .
^ Karin M, Delhase M (August 1998). "JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action?" . Proceedings of the National Academy of Sciences of the United States of America . 95 (16): 9067–9069. Bibcode :1998PNAS...95.9067K . doi :10.1073/pnas.95.16.9067 . PMC 33875 . PMID 9689033 .
^ a b Charlaftis N, Suddason T, Wu X, Anwar S, Karin M, Gallagher E (November 2014). "The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines" . The EMBO Journal . 33 (21): 2581–2596. doi :10.15252/embj.201488351 . PMC 4282369 . PMID 25260751 .
^ Glubb DM, Maranian MJ, Michailidou K, Pooley KA, Meyer KB, Kar S, et al. (January 2015). "Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1" . American Journal of Human Genetics . 96 (1): 5–20. doi :10.1016/j.ajhg.2014.11.009 . PMC 4289692 . PMID 25529635 .
^ Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. (June 2007). "Genome-wide association study identifies novel breast cancer susceptibility loci" . Nature . 447 (7148): 1087–1093. Bibcode :2007Natur.447.1087E . doi :10.1038/nature05887 . PMC 2714974 . PMID 17529967 .
^ "Q13233 (M3K1_HUMAN)" . Swiss Model . Swiss Institute of Bioinformatics.
^ Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ (22–29 December 1994). "Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1". Nature . 372 (6508): 798–800. Bibcode :1994Natur.372..798Y . doi :10.1038/372798a0 . PMID 7997270 . S2CID 4369739 .
^ Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T (May 2002). "The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2" . Molecular Cell . 9 (5): 945–956. doi :10.1016/s1097-2765(02)00519-1 . PMID 12049732 .
^ Filipčík P, Latham SL, Cadell AL, Day CL, Croucher DR, Mace PD (September 2020). "A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers" . Proceedings of the National Academy of Sciences of the United States of America . 117 (35): 21308–21318. Bibcode :2020PNAS..11721308F . doi :10.1073/pnas.2006429117 . PMC 7474687 . PMID 32817551 .
^ "HomoloGene - NCBI" . www.ncbi.nlm.nih.gov . Retrieved 2020-05-01 .
^ Juriloff DM, Harris MJ, Mah DG (January 2005). "The open-eyelid mutation, lidgap-Gates, is an eight-exon deletion in the mouse Map3k1 gene". Genomics . 85 (1): 139–142. doi :10.1016/j.ygeno.2004.10.002 . PMID 15607429 .
^ Yujiri T, Sather S, Fanger GR, Johnson GL (December 1998). "Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption". Science . 282 (5395): 1911–1914. Bibcode :1998Sci...282.1911Y . doi :10.1126/science.282.5395.1911 . PMID 9836645 .
^ Yujiri T, Ware M, Widmann C, Oyer R, Russell D, Chan E, et al. (June 2000). "MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation" . Proceedings of the National Academy of Sciences of the United States of America . 97 (13): 7272–7277. Bibcode :2000PNAS...97.7272Y . doi :10.1073/pnas.130176697 . PMC 16535 . PMID 10852963 .
^ Yujiri T, Fanger GR, Garrington TP, Schlesinger TK, Gibson S, Johnson GL (April 1999). "MEK kinase 1 (MEKK1) transduces c-Jun NH2-terminal kinase activation in response to changes in the microtubule cytoskeleton" . The Journal of Biological Chemistry . 274 (18): 12605–12610. doi :10.1074/jbc.274.18.12605 . PMID 10212239 . S2CID 37158636 .
^ Minamino T, Yujiri T, Papst PJ, Chan ED, Johnson GL, Terada N (December 1999). "MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes" . Proceedings of the National Academy of Sciences of the United States of America . 96 (26): 15127–15132. Bibcode :1999PNAS...9615127M . doi :10.1073/pnas.96.26.15127 . PMC 24784 . PMID 10611349 .
^ Zhang L, Wang W, Hayashi Y, Jester JV, Birk DE, Gao M, et al. (September 2003). "A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure" . The EMBO Journal . 22 (17): 4443–4454. doi :10.1093/emboj/cdg440 . PMC 202382 . PMID 12941696 .
^ Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC, Karin M (October 2004). "Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch" . Science . 306 (5694): 271–275. Bibcode :2004Sci...306..271G . doi :10.1126/science.1099414 . PMID 15358865 . S2CID 31876966 .
^ Gallagher E, Enzler T, Matsuzawa A, Anzelon-Mills A, Otero D, Holzer R, et al. (January 2007). "Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production". Nature Immunology . 8 (1): 57–63. doi :10.1038/ni1421 . PMID 17143273 . S2CID 23344995 .
^ Bonnesen B, Orskov C, Rasmussen S, Holst PJ, Christensen JP, Eriksen KW, et al. (November 2005). "MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver" . Blood . 106 (10): 3396–3404. doi :10.1182/blood-2005-04-1739 . PMID 16081685 . S2CID 19307521 .
^ Labuda T, Christensen JP, Rasmussen S, Bonnesen B, Karin M, Thomsen AR, Odum N (August 2006). "MEK kinase 1 is a negative regulator of virus-specific CD8(+) T cells" . European Journal of Immunology . 36 (8): 2076–2084. doi :10.1002/eji.200535163 . PMID 16761309 . S2CID 12332084 .
^ Suddason T, Anwar S, Charlaftis N, Gallagher E (January 2016). "T-Cell-Specific Deletion of Map3k1 Reveals the Critical Role for Mekk1 and Jnks in Cdkn1b-Dependent Proliferative Expansion" . Cell Reports . 14 (3): 449–457. doi :10.1016/j.celrep.2015.12.047 . PMC 4733086 . PMID 26774476 .
^ Kwan R, Burnside J, Kurosaki T, Cheng G (November 2001). "MEKK1 is essential for DT40 cell apoptosis in response to microtubule disruption" . Molecular and Cellular Biology . 21 (21): 7183–7190. doi :10.1128/MCB.21.21.7183-7190.2001 . PMC 99893 . PMID 11585901 .
^ a b Tricker E, Arvand A, Kwan R, Chen GY, Gallagher E, Cheng G (February 2011). "Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1" . PLOS ONE . 6 (2): e17310. Bibcode :2011PLoSO...617310T . doi :10.1371/journal.pone.0017310 . PMC 3045432 . PMID 21364884 .
^ "MEKK1 (human)" . www.phosphosite.org . Retrieved 2020-02-26 .
^ Khokhlatchev A, Xu S, English J, Wu P, Schaefer E, Cobb MH (April 1997). "Reconstitution of mitogen-activated protein kinase phosphorylation cascades in bacteria. Efficient synthesis of active protein kinases" . The Journal of Biological Chemistry . 272 (17): 11057–11062. doi :10.1074/jbc.272.17.11057 . PMID 9110999 .
^ Lee SY, Reichlin A, Santana A, Sokol KA, Nussenzweig MC, Choi Y (November 1997). "TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival" . Immunity . 7 (5): 703–713. doi :10.1016/s1074-7613(00)80390-8 . PMID 9390693 .
^ Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S, et al. (September 2006). "Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling". Nature Immunology . 7 (9): 962–970. doi :10.1038/ni1367 . PMID 16862162 . S2CID 34181754 .
^ Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, et al. (November 2005). "Essential function for the kinase TAK1 in innate and adaptive immune responses". Nature Immunology . 6 (11): 1087–1095. doi :10.1038/ni1255 . PMID 16186825 . S2CID 13005309 .
^ Gallagher E, Enzler T, Matsuzawa A, Anzelon-Mills A, Otero D, Holzer R, et al. (January 2007). "Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production". Nature Immunology . 8 (1): 57–63. doi :10.1038/ni1421 . PMID 17143273 . S2CID 23344995 .
^ Matsuzawa A, Tseng PH, Vallabhapurapu S, Luo JL, Zhang W, Wang H, et al. (August 2008). "Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex" . Science . 321 (5889): 663–668. Bibcode :2008Sci...321..663M . doi :10.1126/science.1157340 . PMC 2669719 . PMID 18635759 .
^ Karin M, Gallagher E (March 2009). "TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes". Immunological Reviews . 228 (1): 225–240. doi :10.1111/j.1600-065X.2008.00755.x . PMID 19290931 . S2CID 1683105 .
^ a b Charlaftis N, Suddason T, Wu X, Anwar S, Karin M, Gallagher E (November 2014). "The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines" . The EMBO Journal . 33 (21): 2581–2596. doi :10.15252/embj.201488351 . PMC 4282369 . PMID 25260751 .
^ Xia Y, Makris C, Su B, Li E, Yang J, Nemerow GR, Karin M (May 2000). "MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration" . Proceedings of the National Academy of Sciences of the United States of America . 97 (10): 5243–5248. Bibcode :2000PNAS...97.5243X . doi :10.1073/pnas.97.10.5243 . PMC 25813 . PMID 10805784 .
^ "MAP3K1 - My Cancer Genome" . www.mycancergenome.org . Retrieved 2020-02-26 .
^ a b "MAP3K1 mitogen-activated protein kinase kinase kinase 1 [Homo sapiens (human)] - Gene - NCBI" . www.ncbi.nlm.nih.gov . Retrieved 2020-05-02 .
^ Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. (May 2012). "The landscape of cancer genes and mutational processes in breast cancer" . Nature . 486 (7403): 400–404. Bibcode :2012Natur.486..400. . doi :10.1038/nature11017 . PMC 3428862 . PMID 22722201 .
^ Shojo K, Kosaka T, Nakamura K, Hongo H, Kobayashi H, Mikami S, et al. (May 2021). "First case of ductal adenocarcinoma of the prostate with MAP3K1 homozygous deletion" . IJU Case Reports . 4 (3): 176–179. doi :10.1002/iju5.12274 . PMC 8088887 . PMID 33977253 .
^ Zhang C, Feng S, Tu Z, Sun J, Rui T, Zhang X, et al. (September 2021). "Sarcomatoid hepatocellular carcinoma: From clinical features to cancer genome" . Cancer Medicine . 10 (18): 6227–6238. doi :10.1002/cam4.4162 . PMC 8446410 . PMID 34331411 .
^ Morrell ED, O'Mahony DS, Glavan BJ, Harju-Baker S, Nguyen C, Gunderson S, et al. (January 2018). "Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome" . American Journal of Respiratory Cell and Molecular Biology . 58 (1): 117–125. doi :10.1165/rcmb.2017-0030OC . PMC 5941309 . PMID 28858533 .
^ Nelson DS, van Halteren A, Quispel WT, van den Bos C, Bovée JV, Patel B, et al. (June 2015). "MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis" . Genes, Chromosomes & Cancer . 54 (6): 361–368. doi :10.1002/gcc.22247 . PMID 25899310 . S2CID 6264217 .
^ Pearlman A, Loke J, Le Caignec C, White S, Chin L, Friedman A, et al. (December 2010). "Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination" . American Journal of Human Genetics . 87 (6): 898–904. doi :10.1016/j.ajhg.2010.11.003 . PMC 2997363 . PMID 21129722 .
^ Goto M, Chow J, Muramoto K, Chiba K, Yamamoto S, Fujita M, et al. (November 2009). "E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione], a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1: in vitro characterization of its anti-inflammatory and antihyperproliferative activities". The Journal of Pharmacology and Experimental Therapeutics . 331 (2): 485–495. doi :10.1124/jpet.109.156554 . PMID 19684251 . S2CID 37755563 .
^ Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways" . The Journal of Biological Chemistry . 277 (20): 17706–17712. doi :10.1074/jbc.M111982200 . PMID 11884395 .
^ Zhang Y, Neo SY, Han J, Lin SC (August 2000). "Dimerization choices control the ability of axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase" . The Journal of Biological Chemistry . 275 (32): 25008–25014. doi :10.1074/jbc.M002491200 . PMID 10829020 .
^ Karandikar M, Xu S, Cobb MH (December 2000). "MEKK1 binds raf-1 and the ERK2 cascade components" . The Journal of Biological Chemistry . 275 (51): 40120–40127. doi :10.1074/jbc.M005926200 . PMID 10969079 .
^ Pomérance M, Multon MC, Parker F, Venot C, Blondeau JP, Tocqué B, Schweighoffer F (September 1998). "Grb2 interaction with MEK-kinase 1 is involved in regulation of Jun-kinase activities in response to epidermal growth factor" . The Journal of Biological Chemistry . 273 (38): 24301–24304. doi :10.1074/jbc.273.38.24301 . PMID 9733714 .
^ Xu S, Cobb MH (December 1997). "MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases" . The Journal of Biological Chemistry . 272 (51): 32056–32060. doi :10.1074/jbc.272.51.32056 . PMID 9405400 .
^ Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (May 1999). "Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain" . Genes & Development . 13 (10): 1297–1308. doi :10.1101/gad.13.10.1297 . PMC 316725 . PMID 10346818 .
^ Saltzman A, Searfoss G, Marcireau C, Stone M, Ressner R, Munro R, et al. (April 1998). "hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity" . FEBS Letters . 425 (3): 431–435. doi :10.1016/s0014-5793(98)00287-7 . PMID 9563508 . S2CID 84816080 .
^ Gallagher ED, Gutowski S, Sternweis PC, Cobb MH (January 2004). "RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity" . The Journal of Biological Chemistry . 279 (3): 1872–1877. doi :10.1074/jbc.M309525200 . PMID 14581471 .
^ Fanger GR, Johnson NL, Johnson GL (August 1997). "MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42" . The EMBO Journal . 16 (16): 4961–4972. doi :10.1093/emboj/16.16.4961 . PMC 1170131 . PMID 9305638 .
^ Christerson LB, Gallagher E, Vanderbilt CA, Whitehurst AW, Wells C, Kazempour R, et al. (August 2002). "p115 Rho GTPase activating protein interacts with MEKK1". Journal of Cellular Physiology . 192 (2): 200–208. doi :10.1002/jcp.10125 . PMID 12115726 . S2CID 33717402 .
^ Xia Y, Wu Z, Su B, Murray B, Karin M (November 1998). "JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension" . Genes & Development . 12 (21): 3369–3381. doi :10.1101/gad.12.21.3369 . PMC 317229 . PMID 9808624 .
^ Yujiri T, Nawata R, Takahashi T, Sato Y, Tanizawa Y, Kitamura T, Oka Y (February 2003). "MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression" . The Journal of Biological Chemistry . 278 (6): 3846–3851. doi :10.1074/jbc.M206087200 . PMID 12458213 .
Lin, A (2006). "The JNK Signaling Pathway (Molecular Biology Intelligence Unit)". Landes Bioscience . 1 : 1–97. ISBN 978-1587061202 .
Activity Regulation Classification Kinetics Types