Alternative titles; symbols
HGNC Approved Gene Symbol: MAPK9
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:180,233,143-180,292,083 (from NCBI)
The transcriptional activity of the c-Jun protooncoprotein (see 165160) is augmented through phosphorylation at 2 sites by c-Jun amino-terminal kinases (JNKs). Using in-gel kinase assays, Hibi et al. (1993) identified 2 JNKs, 46 and 55 kD in size. The 46-kD protein JNK1 (601158) was shown to be a member of the mitogen-activated protein kinase (MAPK) family. Using a JNK1 cDNA as a probe, Kallunki et al. (1994) and Sluss et al. (1994) isolated cDNAs encoding the 55-kD protein, which both designated JNK2. Kallunki et al. (1994) reported that the sequence of the predicted 424-amino acid JNK2 protein is 83% identical to that of JNK1. Both JNKs contain a thr-pro-tyr phosphorylation motif. Northern blot analysis revealed that JNK2 is expressed as multiple transcripts in many cell types.
By analysis of brain cDNAs, Gupta et al. (1996) identified 10 JNK isoforms, 4 of which are produced by alternative splicing of JNK2. Isoforms of 46 and 55 kD are encoded by both the JNK1 and JNK2 genes. The JNK isoforms differ in their interactions with transcription factors ATF2 (CREB2; 123811), ELK1 (311040), and Jun.
Kallunki et al. (1994) showed that expression of JNK2 in mammalian cells potentiated activation of a c-Jun-responsive promoter, while expression of JNK1 had no effect. Using in vitro binding assays, they found that JNK2 bound c-Jun approximately 25 times more efficiently than did JNK1. The authors traced this difference to a small beta-strand-like region near the catalytic pocket of the enzyme. Sluss et al. (1994) demonstrated that both UV radiation and the proinflammatory cytokine TNF-alpha (191160) induce JNK1 and JNK2.
Direct association of p53 (191170) with the cellular protein MDM2 (164785) results in ubiquitination and subsequent degradation of p53. Based on evidence for JNK association with p53, Fuchs et al. (1998) sought to elucidate the role of nonactive JNK2 in regulating p53 stability. The amount of p53-JNK complex was inversely correlated with the p53 level. A peptide corresponding to the JNK binding site on p53 efficiently blocked ubiquitination of p53. Similarly, p53 lacking the JNK binding site exhibited a longer half-life than wildtype p53. Outcompeting JNK association with p53 increased the level of p53, whereas overexpression of a phosphorylation mutant form of JNK inhibited p53 accumulation. JNK-p53 and MDM2-p53 complexes were preferentially found in G0/G1 and S/G2M phases of the cell cycle, respectively. Altogether, these data indicated that JNK is an MDM2-independent regulator of p53 stability in nonstressed cells.
Gao et al. (2004) found that in the case of c-JUN (165160) and JUNB (165161), extracellular stimuli modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation. Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) cascade after T cell stimulation accelerated degradation of c-JUN and JUNB through phosphorylation-dependent activation of the E3 ligase ITCH (606409). Gao et al. (2004) found that this pathway modulates cytokine production by effector T cells.
Cell stress is accompanied by downregulated rRNA synthesis. Mayer et al. (2005) found that stress-dependent inhibition of RNA polymerase I (Pol I; see 602000) was mediated by inactivation of the Pol I-specific transcription factor TIFIA (RRN3; 605121) in mammalian cells. Inactivation was due to JNK2 phosphorylation of TIFIA at residue thr200, which impaired TIFIA interaction with Pol I and the TBP (600075)-containing complex TIFIB/SL1 (see 604903), thereby abrogating initiation complex formation.
Gupta et al. (1996) mapped the MAPK9 gene to 5q35 by fluorescence in situ hybridization.
Kuan et al. (1999) and Sabapathy et al. (1999) studied the role of Jnk1 and Jnk2 in mouse brain development and found that compound mutant mice were embryonic lethal. Both groups found similar defects in brain development due to dysregulation of apoptosis. Kuan et al. (1999) described reduced cell death in the lateral edges of the hindbrain prior to neural tube closure. On the other hand, mutant forebrains showed increased apoptosis and caspase activation, leading to precocious degeneration. Kuan et al. (1999) noted that mice deficient in either protein alone developed normally, and they hypothesized that Jnk1 and Jnk2 play redundant but critical roles in the regulation of regional specific apoptosis during early brain development.
Tournier et al. (2000) demonstrated that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of JNK1 and JNK2 genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicated that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
Yang et al. (1998) found that differentiation of precursor CD4 (186940)-positive T cells into effector T-helper-1 (Th1) cells was impaired in Jnk2-deficient mice upon antigen stimulation. Differentiation into T-helper-2 (Th2) cells was not affected. The inability of IL12 (see 161560) to differentiate CD4-positive T cells into effector Th1 cells was due to a defect in gamma-interferon (IFNG; 147570) production during the early stages of differentiation. Addition of exogenous IFNG during differentiation restored IL12-stimulated Th1 cell differentiation in Jnk2-deficient mice.
Sabapathy et al. (1999) found that Jnk2-null mice were deficient in activation of peripheral T cells but not B cells. Jnk2 functioned in a cell type-specific and stimulus-dependent manner. It was required for apoptosis of immature thymocytes induced by anti-CD3 (see 186780) antibody, but not for apoptosis induced by anti-Fas (134637) antibody, ultraviolet-C radiation, or dexamethasone exposure. Activation-induced apoptosis of mature T cells proceeded normally in the absence of Jnk2.
Dong et al. (2000) used 3 new mouse models in which peripheral T cells completely lack JNK proteins or signaling to test whether the JNK signaling pathway is crucial for IL2 expression and T-cell activation. Unexpectedly, these T cells made more IL2 (147680) and proliferated better than wildtype cells. However, production of effector T-cell cytokines did require JNK. Thus, Dong et al. (2000) concluded that JNK is necessary for T-cell differentiation but not for naive T-cell activation.
Han et al. (2002) studied the development of inflammatory arthritis in Jnk2-null mice following exposure to anti-type II collagen antibodies. Clinical arthritis was slightly more severe in the Jnk2-null animals, although safranin O-staining of joint sections suggested slightly less cartilage damage. There was no effect on other markers of inflammatory arthritis.
Roles for JNK in the developing nervous system and T-cell-mediated immunity have been established by detailed studies of mice with compound mutations in the Jnk genes. To study the roles of JNK in other mammalian tissues, Weston et al. (2004) studied mice lacking both of the ubiquitously expressed isoforms (Jnk1 and Jnk2). These mice died during midgestation with neural tube closure defects and brain abnormalities. Jnk-deficient mice exhibited delayed epithelial development in the epidermis, intestines, and lungs. In addition, Jnk-deficient mice exhibited an eyelid closure defect associated with markedly reduced epidermal growth factor (EGF; 131530) receptor (EGFR; 131550) function and loss of expression of the ligand Egf. Adult mice lacking either Jnk1 or Jnk2 displayed striking differences in epidermal proliferation and differentiation, indicative of distinct roles for these kinases in the skin. Weston et al. (2004) concluded that JNK is necessary for epithelial morphogenesis and is an essential regulator of signal transduction by the EGF receptor in the epidermis.
Ricci et al. (2004) showed that atherosclerosis-prone ApoE (107741)-null mice simultaneously lacking Jnk2 (ApoE -/- Jnk2 -/- mice), but not ApoE -/- Jnk1 -/- mice, developed less atherosclerosis than do ApoE-null mice. Pharmacologic inhibition of Jnk activity efficiently reduced plaque formation. Macrophages lacking Jnk2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SRA, or MSR1; 153622), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of Jnk2 was sufficient to decrease atherogenesis. Thus, Ricci et al. (2004) concluded that JNK2-dependent phosphorylation of SRA promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis.
Jaeschke et al. (2005) found that disruption of the Mapk9 gene in nonobese diabetic (NOD) mice decreased autoimmune-mediated insulinitis and reduced disease progression to diabetes. Cd4-positive T cells from Mapk9-deficient NOD mice produced less Ifng, but significantly increased amounts of Il4 (147780) and Il5 (147850). Jaeschke et al. (2005) concluded that MAPK9 has a role in controlling the Th1/Th2 balance of the immune response, thereby providing protection against autoimmune diabetes.
Tuncman et al. (2006) intercrossed Jnk1-null and Jnk2-null mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. The authors observed reduced body weight and increased insulin sensitivity only in Jnk1-null mice and in Jnk1 +/- Jnk2-null mice. These 2 groups of mice also exhibited reduced total Jnk activity and cytokine expression in liver tissue compared with all other genotypes examined. Tuncman et al. (2006) concluded that, like JNK1, JNK2 is involved in metabolic regulation, but its function is not obvious because of regulatory crosstalk between the 2 isoforms.
Dong, C., Yang, D. D., Tournier, C., Whitmarsh, A. J., Xu, J., Davis, R. J., Flavell, R. A. JNK is required for effector T-cell function but not for T-cell activation. Nature 405: 91-94, 2000. [PubMed: 10811224] [Full Text: https://doi.org/10.1038/35011091]
Fuchs, S. Y., Adler, V., Buschmann, T., Yin, Z., Wu, X., Jones, S. N., Ronai, Z. JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev. 12: 2658-2663, 1998. [PubMed: 9732264] [Full Text: https://doi.org/10.1101/gad.12.17.2658]
Gao, M., Labuda, T., Xia, Y., Gallagher, E., Fang, D., Liu, Y.-C., Karin, M. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306: 271-275, 2004. [PubMed: 15358865] [Full Text: https://doi.org/10.1126/science.1099414]
Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, H. K., Derijard, B., Davis, R. J. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15: 2760-2770, 1996. [PubMed: 8654373]
Han, Z., Chang, L., Yamanishi, Y., Karin, M., Firestein, G. S. Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis. Arthritis Rheum. 46: 818-823, 2002. [PubMed: 11920420] [Full Text: https://doi.org/10.1002/art.10104]
Hibi, M., Lin, A., Smeal, T., Minden, A., Karin, M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7: 2135-2148, 1993. [PubMed: 8224842] [Full Text: https://doi.org/10.1101/gad.7.11.2135]
Jaeschke, A., Rincon, M., Doran, B., Reilly, J., Neuberg, D., Greiner, D. L., Shultz, L. D., Rossini, A. A., Flavell, R. A., Davis, R. J. Disruption of the Jnk2 (Mapk9) gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes. Proc. Nat. Acad. Sci. 102: 6931-6935, 2005. [PubMed: 15867147] [Full Text: https://doi.org/10.1073/pnas.0502143102]
Kallunki, T., Su, B., Tsigelny, I., Sluss, H. K., Derijard, B., Moore, G., Davis, R., Karin, M. JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 8: 2996-3007, 1994. [PubMed: 8001819] [Full Text: https://doi.org/10.1101/gad.8.24.2996]
Kuan, C.-Y., Yang, D. D., Roy, D. R. S., Davis, R. J., Rakic, P., Flavell, R. A. The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22: 667-676, 1999. [PubMed: 10230788] [Full Text: https://doi.org/10.1016/s0896-6273(00)80727-8]
Mayer, C., Bierhoff, H., Grummt, I. The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. Genes Dev. 19: 933-941, 2005. [PubMed: 15805466] [Full Text: https://doi.org/10.1101/gad.333205]
Ricci, R., Sumara, G., Sumara, I., Rozenberg, I., Kurrer, M., Akhmedov, A., Hersberger, M., Eriksson, U., Eberli, F. R., Becher, B., Boren, J., Chen, M., Cybulsky, M. I., Moore, K. J., Freeman, M. W., Wagner, E. F., Matter, C. M., Luscher, T. F. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science 306: 1558-1561, 2004. [PubMed: 15567863] [Full Text: https://doi.org/10.1126/science.1101909]
Sabapathy, K., Hu, Y., Kallunki, T., Schreiber, M., David, J.-P., Jochum, W., Wagner, E. F., Karin, M. JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr. Biol. 9: 116-125, 1999. [PubMed: 10021384] [Full Text: https://doi.org/10.1016/s0960-9822(99)80065-7]
Sabapathy, K., Jochum, W., Hochedlinger, K., Chang, L., Karin, M., Wagner, E. F. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech. Dev. 89: 115-124, 1999. [PubMed: 10559486] [Full Text: https://doi.org/10.1016/s0925-4773(99)00213-0]
Sluss, H. K., Barrett, T., Derijard, B., Davis, R. J. Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Molec. Cell Biol. 14: 8376-8384, 1994. [PubMed: 7969172] [Full Text: https://doi.org/10.1128/mcb.14.12.8376-8384.1994]
Tournier, C., Hess, P., Yang, D. D., Xu, J., Turner, T. K., Nimnual, A., Bar-Sagi, D., Jones, S. N., Flavell, R. A., Davis, R. J. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288: 870-874, 2000. [PubMed: 10797012] [Full Text: https://doi.org/10.1126/science.288.5467.870]
Tuncman, G., Hirosumi, J., Solinas, G., Chang, L., Karin, M., Hotamisligil, G. S. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Nat. Acad. Sci. 103: 10741-10746, 2006. [PubMed: 16818881] [Full Text: https://doi.org/10.1073/pnas.0603509103]
Weston, C. R., Wong, A., Hall, J. P., Goad, M. E. P., Flavell, R. A., Davis, R. J. The c-Jun NH2-terminal kinase is essential for epidermal growth factor expression during epidermal morphogenesis. Proc. Nat. Acad. Sci. 101: 14114-14119, 2004. [PubMed: 15375216] [Full Text: https://doi.org/10.1073/pnas.0406061101]
Yang, D. D., Conze, D., Whitmarsh, A. J., Barrett, T., Davis, R. J., Rincon, M., Flavell, R. A. Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2. Immunity 9: 575-585, 1998. [PubMed: 9806643] [Full Text: https://doi.org/10.1016/s1074-7613(00)80640-8]