Alternative titles; symbols
HGNC Approved Gene Symbol: MAP2K4
Cytogenetic location: 17p12 Genomic coordinates (GRCh38): 17:12,020,877-12,143,828 (from NCBI)
At least 3 mitogen-activated protein kinase (MAPK) cascades exist in mammals, each consisting of a 3-kinase module composed of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK). JUN N-terminal kinases (JNKs; see 601158) are MAPKs that stimulate transcriptional activity of JUN (165160) in response to growth factors, proinflammatory cytokines, and certain environmental stresses, such as ultraviolet light or osmotic shock. MAP2K4 is a MAPKK that directly activates the JNKs, as well as the related MAPK p38 (MAPK14; 600289) (Wu et al., 1997).
By screening a human T-lymphocyte Jurkat cDNA library with a mouse cDNA encoding Mma1-Sek1, a potential MAPKK, Lin et al. (1995) identified a human homolog of Mma1-Sek1, which they named JNKK. The deduced 399-amino acid JNKK protein shares more than 95% sequence similarity with Mma1-Sek1 in the kinase domain. JNKK is also similar to S. cerevisiae Pbs2.
One Ras-dependent protein kinase cascade leading from growth factor receptors to the extracellular signal-regulated kinase (ERK) subgroup of MAPKs is dependent on the protein kinase RAF1 (164760), which activates the MAPK/ERK kinase (MEK) dual-specificity kinases. A second protein kinase cascade leading to activation of the JNKs is dependent on MEK kinase (MEKK). Lin et al. (1995) found that JNKK was a dual-specificity kinase that activated JNK and functioned between MEKK and JNK. JNKK activated the JNKs, but not the ERKs, and was unresponsive to RAF1 in transfected HeLa cells. It also activated another MAPK, p38, whose activity is regulated similarly to that of the JNKs. Lin et al. (1995) also showed that human JNKK could partially complement Pbs2 deficiency in yeast.
The stress-activated protein kinase (SAPK) and MAPK pathways are signal transduction cascades with distinct functions in mammals. White et al. (1996) noted that they are structurally related in their phosphorylation activity but differ in the events leading to phosphorylation. MAPKs are rapidly phosphorylated and activated in response to various extracellular stimuli. MAPK is regulated by its own phosphorylation by MAPK kinases (MAP2Ks), e.g., MAP2K1 (176872) and MAP2K6 (601254). In the SAPK pathway, SAPKs are the dominant JNKs activated in response to a variety of cellular stresses, including treatment with interleukin-beta (147720) and tumor necrosis factor-alpha (TNFA, or TNF; 191160). MAP2K4, or SERK1, is a potent physiologic activator of SAPKs.
Wu et al. (1997) showed that JNKK1 was a specific activator of JNK1 (601158), JNK2 (602896), and p38, but not of ERK2 (176948). Among MEKK1 (600982), MEKK2 (MAP3K2; 609487), GCK, and ASK (MEKK5), MEKK1 was the most potent activator of JNKK1, followed by MEKK2; GCK and ASK only slightly activated JNKK1.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the ERK, JNK, and p38 MAPK pathways and inhibition of the nuclear factor kappa B (NF-kappa-B) pathway. The expression of YopJ has been correlated with the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al. (1999) identified mammalian binding partners of YopJ. These included the fusion proteins of the GAL4 activation domain with MAPK kinases MKK1 (176872), MKK2 (601263), and MKK4/SEK1. YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3 (602315), MKK4, and MKK5 (602448). Binding of YopJ to the MKK blocked both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection.
Using a yeast 2-hybrid screen, McDonald et al. (2000) identified JNK3 (602897) as a binding partner of beta-arrestin-2 (ARBB2; 107941). These results were confirmed by coimmunoprecipitation from mouse brain extracts and cotransfection in COS-7 cells. The upstream JNK activators apoptosis signal-regulating kinase-1 (ASK1; 602448) and MKK4 were also found in complex with ARBB2. Cellular transfection of ARBB2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor (AGTR1; 106165) activated JNK3 and triggered the colocalization of ARBB2 and active JNK3 to intracellular vesicles. Thus, McDonald et al. (2000) concluded that ARBB2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a G protein-coupled receptor.
Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Integrated analysis of somatic mutations and copy number alterations identified 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 in oncogenesis.
Toll-like receptors (TLRs; see 603030) play a critical role in the initiation of immune responses against invading pathogens. Lai et al. (2013) found that stimulation of mouse peritoneal macrophages with various TLR ligands reduced expression of microRNA-92A (MIR92A; see 609422) and most Mir92a family members. Decreased Mir92a expression enhanced TLR-associated signaling events by increasing activation of the JNK pathway, thereby promoting production of proinflammatory cytokines, such as Il6 (147620) and Tnfa. Luciferase and knockdown analyses showed that Mir92a directly targeted mouse Mkk4 and reduced TLR-induced inflammatory responses.
By radiation hybrid mapping, Rampoldi et al. (1997) assigned genes involved in the MAPK cascade to specific chromosomal sites, including MEK4, which they mapped to chromosome 17p12.
White et al. (1996) mapped the human and mouse genes encoding MAP2K4, which they called SERK1. The human gene was assigned to chromosome 17 by PCR analysis of hamster/human somatic cell hybrids containing a single human chromosome. White et al. (1996) stated that MAP2K4 localized to chromosome 17p11 by fluorescence in situ hybridization. In mouse, they mapped the Map2k4 gene to chromosome 11 by analysis of interspecific backcrosses. The mouse gene maps to a region with extensive homology of synteny to human chromosome 17p11.2.
Somatic Mutations in Pancreatic Cancer
Biankin et al. (2012) performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort of 142 patients with early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumors identified substantial heterogeneity with 2,016 nonsilent mutations and 1,628 copy number variations. Biankin et al. (2012) defined 16 significantly mutated genes, reaffirming known mutations and uncovering novel mutated genes including additional genes involved in chromatin modification (EPC1, 610999 and ARID2, 609539), DNA damage repair (ATM; 607585), and other mechanisms (ZIM2 (see 601483); MAP2K4; NALCN, 611549; SLC16A4, 603878; and MAGEA6, 300176). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signaling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. Biankin et al. (2012) also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
To define the role of SEK1 in vivo, Ganiatsas et al. (1998) studied stress-induced signaling in embryonic stem and fibroblast cells homozygous for an Sek1 knockout and evaluated the phenotype of Sek1 -/- mouse embryos during development. Sek1-deficient embryonic stem cells showed defects in stimulated SAPK phosphorylation but not in the phosphorylation of p38 kinase. In contrast, Sek1-deficient fibroblasts exhibited defects in both SAPK and p38 phosphorylation, demonstrating that crosstalk exists between the stress-activated cascades. Tumor necrosis factor-alpha and interleukin-1 (see 147760) stimulation of both stress-activated cascades was severely affected in the Sek1-deficient fibroblasts. Sek1 deficiency led to embryonic lethality after embryonic day 12.5 and was associated with abnormal liver development. The phenotype was similar to that of the Jun-null mouse embryos (165160) and suggested that SEK1 is required for phosphorylation and activation of JUN during organogenesis of the liver.
Using a forward genetic screen of C. elegans mutants, Kim et al. (2002) showed that viable worms lacking esp2 and esp8, homologs of the mammalian MAP kinases SEK1 and ASK1, were highly susceptible to and died more rapidly from both a gram-negative bacterium, P. aeruginosa, and a gram-positive organism, E. faecalis, than wildtype worms. RNA-interference and biochemical analyses likewise implicated the p38 MAP kinase (MAPK14; 600289) homolog, pmk1, in susceptibility to these pathogens. Kim et al. (2002) concluded that MAP kinase signaling, which is also involved in plant pathogen resistance, is a conserved element in innate metazoan immunity to diverse pathogens.
Wang et al. (2007) targeted Mkk4 deletion to the neural lineage in mice. Homozygous mutant mice were indistinguishable from control littermates at birth, but they stopped growing a few days later and died. Mutant mice displayed severe neurologic defects, including misalignment of Purkinje cells in cerebellum and delayed radial migration in cerebral cortex. Decreased Jnk activity due to Mkk4 deficiency correlated with impaired phosphorylation of a subset of Jnk substrates and with altered gene expression.
Knockout of Fah (613871) causes liver failure in mice due to accumulation of intermediary hepatotoxins generated during incomplete tyrosine catabolism. Lethality can be prevented by continuous treatment with the drug nitisinone (NTBC). Wuestefeld et al. (2013) coupled NTBC withdrawal in Fah -/- mice with short hairpin RNAs to identify genes that influence liver failure and regeneration. They found that stable knockdown of Mkk4 robustly increased the regenerative capacity of hepatocytes and reduced the number of apoptotic hepatocytes in Fah -/- mice following NTBC withdrawal, as well as in mouse models of acute and chronic liver failure. Inhibition of Mkk4 resulted in faster cell-cycle entry and progression of hepatocytes during liver regeneration by compensatory upregulation of Mkk7 (MAP2K7; 603014) and Jnk1-dependent activation of Atf2 (123811) and Elk1 (311040). Inhibition of Jnk1, but not Jnk2, abolished the proregenerative effect of Mkk4 knockdown. Wuestefeld et al. (2013) concluded that MKK4 is a master regulator of liver regeneration.
Biankin, A. V., Waddell, N., Kassahn, K. S., Gingras, M.-C., Muthuswamy, L. B., Johns, A. L., Miller, D. K., Wilson, P. J., Patch, A.-M., Wu, J., Chang, D. K., Cowley, M. J., and 116 others. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491: 399-405, 2012. [PubMed: 23103869] [Full Text: https://doi.org/10.1038/nature11547]
Ganiatsas, S., Kwee, L., Fujiwara, Y., Perkins, A., Ikeda, T., Labow, M. A., Zon, L. I. SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Proc. Nat. Acad. Sci. 95: 6881-6886, 1998. [PubMed: 9618507] [Full Text: https://doi.org/10.1073/pnas.95.12.6881]
Kan, Z., Jaiswal, B. S., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H. M., Yue, P., Haverty, P. M., Bourgon, R., Zheng, J., Moorhead, M., Chaudhuri, S., and 20 others. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466: 869-873, 2010. [PubMed: 20668451] [Full Text: https://doi.org/10.1038/nature09208]
Kim, D. H., Feinbaum, R., Alloing, G., Emerson, F. E., Garsin, D. A., Inoue, H., Tanaka-Hino, M., Hisamoto, N., Matsumoto, K., Tan, M.-W., Ausubel, F. M. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297: 623-626, 2002. [PubMed: 12142542] [Full Text: https://doi.org/10.1126/science.1073759]
Lai, L., Song, Y., Liu, Y., Chen, Q., Han, Q., Chen, W., Pan, T., Zhang, Y., Cao, X., Wang, Q. MicroRNA-92a negatively regulates Toll-like receptor (TLR)-triggered inflammatory response in macrophages by targeting MKK4 kinase. J. Biol. Chem. 288: 7956-7967, 2013. [PubMed: 23355465] [Full Text: https://doi.org/10.1074/jbc.M112.445429]
Lin, A., Minden, A., Martinetto, H., Claret, F.-X., Lange-Carter, C., Mercurio, F., Johnson, G. L., Karin, M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 268: 286-290, 1995. [PubMed: 7716521] [Full Text: https://doi.org/10.1126/science.7716521]
McDonald, P. H., Chow, C.-W., Miller, W. E., Laporte, S. A., Field, M. E., Lin, F.-T., Davis, R. J., Lefkowitz, R. J. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290: 1574-1577, 2000. [PubMed: 11090355] [Full Text: https://doi.org/10.1126/science.290.5496.1574]
Orth, K., Palmer, L. E., Bao, Z. Q., Stewart, S., Rudolph, A. E., Bliska, J. B., Dixon, J. E. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285: 1920-1923, 1999. [PubMed: 10489373] [Full Text: https://doi.org/10.1126/science.285.5435.1920]
Rampoldi, L., Zimbello, R., Bortoluzzi, S., Tiso, N., Valle, G., Lanfranchi, G., Danieli, G. A. Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet. Cell Genet. 78: 301-303, 1997. [PubMed: 9465908] [Full Text: https://doi.org/10.1159/000134677]
Wang, X., Nadarajah, B., Robinson, A. C., McColl, B. W., Jin, J.-W., Dajas-Bailador, F., Boot-Handford, R. P., Tournier, C. Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death. Molec. Cell. Biol. 27: 7935-7946, 2007. [PubMed: 17875933] [Full Text: https://doi.org/10.1128/MCB.00226-07]
White, R. A., Hughes, R. T., Adkison, L. R., Bruns, G., Zon, L. I. The gene encoding protein kinase SEK1 maps to mouse chromosome 11 and human chromosome 17. Genomics 34: 430-432, 1996. [PubMed: 8786147] [Full Text: https://doi.org/10.1006/geno.1996.0309]
Wu, Z., Wu, J., Jacinto, E., Karin, M. Molecular cloning and characterization of human JNKK2, a novel jun NH(2)-terminal kinase-specific kinase. Molec. Cell. Biol. 17: 7407-7416, 1997. [PubMed: 9372971] [Full Text: https://doi.org/10.1128/MCB.17.12.7407]
Wuestefeld, T., Pesic, M., Rudalska, R., Dauch, D., Longerich, T., Kang, T.-W., Yevsa, T., Heinzmann, F., Hoenicke, L., Hohmeyer, A., Potapova, A., Rittelmeier, I., and 11 others. A direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153: 389-401, 2013. [PubMed: 23582328] [Full Text: https://doi.org/10.1016/j.cell.2013.03.026]