Alternative titles; symbols
HGNC Approved Gene Symbol: MAPK10
Cytogenetic location: 4q21.3 Genomic coordinates (GRCh38): 4:86,010,405-86,594,074 (from NCBI)
The c-Jun kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family that activate the Jun (see 165160) transcription factor. Gupta et al. (1996) isolated brain cDNAs encoding 10 different JNK isoforms, 8 of which were derived from either JNK1 (601158) or JNK2 (602896). The other 2 cDNAs were from a gene that the authors designated JNK3. JNK3 contains an extended N-terminal region not found in JNK1 or JNK2. The 2 JNK3 isoforms, called JNK3-alpha-1 and JNK3-alpha-2, have different C termini. By SDS-PAGE of in vitro transcription/translation products, Gupta et al. (1996) determined that JNK3-alpha-1 migrates as a 45- to 48-kD doublet and JNK3-alpha-2 migrates as a 54- to 57-kD doublet. They stated that the lower band probably represents translation from a second in-frame start codon that corresponds to the first codon in JNK1 and JNK2. All the JNKs were activated by treatment of cells with the inflammatory cytokine IL1 (see 147720). Multiple JNK isoforms were shown to be inactivated by MKP1 (600714). Comparison of the binding activity of the JNK isoforms demonstrated that they differ in their interactions with the ATF2 (CREB2; 123811), ELK1 (311040), and Jun transcription factors. Gupta et al. (1996) suggested that individual JNKs selectively target specific transcription factors in vivo, providing a mechanism for the generation of tissue-specific responses to the activation of the JNK signal transduction pathway.
Mohit et al. (1995) identified JNK3, or p49-3F12 kinase, as the gene encoding a 49-kD antigen found in the hippocampus and neocortex. The distribution of JNK3-expressing neurons closely matches that of Alzheimer disease targeted neurons in those areas of the brain. Northern blot analysis revealed that JNK3 is expressed as a 2.7-kb mRNA exclusively in the nervous system.
Using a yeast 2-hybrid screen, McDonald et al. (2000) identified JNK3 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 (601335) 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. McDonald et al. (2000) concluded that ARBB2 acts as a scaffold protein that brings the spatial distribution and activity of this MAPK module under the control of a G protein-coupled receptor.
Yoshida et al. (2001) mapped the MAPK10 gene to chromosome 4q21-q22 by fluorescence in situ hybridization and radiation hybrid mapping. They found loss of expression EST markers in the 4q21-q22 region that correspond to the JNK3 gene in 10 of 19 cell lines derived from brain tumors. Together with previous evidence that the Jnk3 signaling pathway mediates apoptosis in central nervous tissue in Jnk3-deficient mice (Yang et al., 1997), the results suggested that loss of expression of the JNK3 gene may play an important role in the development of brain tumors in humans.
Yoshida et al. (2002) determined that the Fas-associated phosphatase-1 gene (PTPN13; 600267) is located only 633 bp upstream from JNK3 in a head-to-head orientation. A short G/C-rich region between the cap sites of the 2 genes suggested that they might share a bidirectional promoter region that appears to contain multiple cis elements.
Shoichet et al. (2006) reported a boy with pharmacoresistant epileptic encephalopathy associated with a heterozygous de novo balanced translocation between chromosome 4 and chromosome Y (Y;4)(q11.2;q21). He was born at term after a normal pregnancy, with birthweight in the normal range. There was no remarkable family history. His early development was also normal. At age 13 months, he presented with atonic seizures and ataxia. He remained interactive (social smile, normal fixation and pursuit). Electroencephalography at this time showed diffuse asynchronous slow spike-wave complexes. Over the next few weeks, his interaction deteriorated, and he developed marked hypotonia and athetoid upper limb movements. He lost fine motor coordination, and he could no longer sit or walk unaided. He also developed tonic seizures and partial complex seizures. Various therapies had little effect on the seizures. He continued to lose motor coordination skills and became progressively less interactive. After age 2 years, he had several episodes of convulsive and nonconvulsive status epilepticus, which were treated with some effect with steroids. A year later, nonconvulsive status epilepticus became quasipersistent despite steroid therapy. The clinical picture was consistent with severe Lennox-Gastaut encephalopathy. Magnetic resonance imaging of the brain at age 7 years was normal. The breakpoint on chromosome 4q was in intron 9 of the JNK3 gene, resulting in a truncated protein lacking kinase activity (602897.0001). Overexpression studies with the mutant protein in various cells lines, including neural cells, indicated that both its solubility and cellular localization differed from that of wildtype JNK3. The authors postulated that the truncated JNK3 protein was defective in the normal JNK3 signal transduction in neuronal cells and in its interaction with beta-arrestin-2 (ARRB2; 107941) and JIP3 (605431), which have roles in neurite outgrowth and neurologic development. Shoichet et al. (2006) suggested that the phenotype of the patient likely resulted from a combination of JNK3 haploinsufficiency and dominant effects of the truncated protein, which probably included both cytotoxic effects and altered protein-protein interactions.
Kunde et al. (2013) reported a 13-year-old boy with delayed psychomotor development and mild intellectual disability without seizures who had a de novo heterozygous balanced translocation, 46,X,t(Y;4)(q12;q21.3), with the breakpoint on 4q falling between exons 8 and 9 of the JNK3 gene. This was predicted to interrupt the coding sequence after nucleotide 730, resulting in truncation and elimination of the conserved kinase domain near the C terminus. In vitro functional expression studies in COS-7 cells showed that both this truncated protein and the truncated protein reported by Shoichet et al. (2006) lacked kinase activity. Coimmunoprecipitation assays showed that the truncated proteins had weaker binding to known JNK-associated scaffold proteins JIP1 (604641) and ARRB2 compared to wildtype. Further immunoprecipitation studies of wildtype JNK3 identified 3 synaptic scaffold proteins, PSD95 (602887), SAP102 (300189), and SHANK3 (606230) as JNK3-interacting partners, and kinase studies suggested that JNK3 phosphorylates PSD95. Patient samples with the truncated JNK3 proteins were not capable of phosphorylating PSD95, although weak binding with PSD95 was observed. Kunde et al. (2013) concluded that both patients had a 50% reduction in classic function of JNK3. Although the presence of truncated protein in patient material could not be validated, dominant-interfering effects of the mutant protein in nervous system tissue could not be excluded. The findings from these 2 unrelated patients suggested that JNK3 mutations are associated with cognitive defects, and that JNK signaling is essential for normal neuronal network formation and cognitive development via interactions with important synaptic proteins.
Kuan et al. (2003) found that Jnk1 was the major JNK isoform responsible for high basal JNK activity in mouse brain. In contrast, targeted deletion of Jnk3 reduced stress-induced JNK activity and protected mice from brain injury after cerebral ischemia-hypoxia. After ischemia-hypoxia, deletion of Jnk3 reduced phosphorylation of c-Jun and induction of Fas receptor (TNFRSF6; 134637), indicating that both may be downstream targets of Jnk3. Wildtype cultured embryonic hippocampal neurons showed diffuse cytochrome c (123970) staining after challenge with oxygen-glucose deprivation, an in vitro model of cerebral ischemia, but Jnk3-null and unchallenged neurons retained cytochrome c inside the mitochondria. Jnk3-null neurons also showed 3 times higher survival after ischemic challenge than wildtype neurons. Kuan et al. (2003) concluded that JNK3 may have a role in stress-induced neuronal apoptosis.
This variant, formerly titled EPILEPTIC ENCEPHALOPATHY, LENNOX-GASTAUT TYPE, has been reclassified as a variant of unknown significance because its contribution to epileptic encephalopathy has not been confirmed.
Shoichet et al. (2006) described truncation of the JNK3 gene at a point within intron 9 in a male patient with developmental epileptic encephalopathy. The patient had a de novo balanced translocation between chromosome 4 and chromosome Y (Y;4)(q11.2;q21). Fluorescence in situ hybridization showed genomic clones from both chromosome 4 and chromosome Y that spanned the breakpoints. Precise mapping of the chromosome 4 breakpoint indicated that the JNK3 gene was disrupted. Expression studies in the patient lymphoblastoid cell line showed that the truncated JNK3 protein was expressed, i.e., the disrupted transcript was not immediately subject to nonsense-mediated mRNA decay as is often the case for truncated mRNAs or those harboring premature termination codons. Overexpression studies with the mutant protein in various cells lines, including neural cells, indicated that both its solubility and cellular localization differed from that of wildtype JNK3. The authors postulated that the truncated JNK3 protein was defective in the normal JNK3 signal transduction in neuronal cells and in its interaction with beta-arrestin-2 (ARRB2) and JIP3 (605431), which have roles in neurite outgrowth and neurologic development. Shoichet et al. (2006) suggested that the phenotype of the patient likely resulted from a combination of JNK3 haploinsufficiency and dominant effects of the truncated protein, which probably included both cytotoxic effects and altered protein-protein interactions.
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]
Kuan, C.-Y., Whitmarsh, A. J., Yang, D. D., Liao, G., Schloemer, A. J., Dong, C., Bao, J., Banasiak, K. J., Haddad, G. G., Flavell, R. A., Davis, R. J., Rakic, P. A critical role for neural-specific JNK3 for ischemic apoptosis. Proc. Nat. Acad. Sci. 100: 15184-15189, 2003. [PubMed: 14657393] [Full Text: https://doi.org/10.1073/pnas.2336254100]
Kunde, S.-A., Rademacher, N., Tzschach, A., Wiedersberg, E., Ullmann, R., Kalscheuer, V. M., Shoichet, S. A. Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients. Hum. Genet. 132: 461-471, 2013. [PubMed: 23329067] [Full Text: https://doi.org/10.1007/s00439-012-1260-5]
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]
Mohit, A. A., Martin, J. H., Miller, C. A. p49(3F12) kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system. Neuron 14: 67-78, 1995. [PubMed: 7826642] [Full Text: https://doi.org/10.1016/0896-6273(95)90241-4]
Shoichet, S. A., Duprez, L., Hagens, O., Waetzig, V., Menzel, C., Herdegen, T., Schweiger, S., Dan, B., Vamos, E., Ropers, H.-H., Kalscheuer, V. M. Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy. Hum. Genet. 118: 559-567, 2006. [PubMed: 16249883] [Full Text: https://doi.org/10.1007/s00439-005-0084-y]
Yang, D. D., Kuan, C. Y., Whitmarsh, A. J., Rincon, M., Zheng, T. S., Davis, R. J., Rakic, P., Flavell, R. A. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389: 865-870, 1997. [PubMed: 9349820] [Full Text: https://doi.org/10.1038/39899]
Yoshida, S., Fukino, K., Harada, H., Nagai, H., Imoto, I., Inazawa, J., Takahashi, H., Teramoto, A., Emi, M. The c-Jun NH2-terminal kinase 3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors. J. Hum. Genet. 46: 182-187, 2001. [PubMed: 11322657] [Full Text: https://doi.org/10.1007/s100380170086]
Yoshida, S., Harada, H., Nagai, H., Fukino, K., Teramoto, A., Emi, M. Head-to-head juxtaposition of Fas-associated phosphatase-1 (FAP-1) and c-Jun NH2-terminal kinase 3 (JNK3) genes: genomic structure and seven polymorphisms of the FAP-1 gene. J. Hum. Genet. 47: 614-619, 2002. [PubMed: 12436199] [Full Text: https://doi.org/10.1007/s100380200094]