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c-Jun N-terminal kinases
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<h2 id="isoforms">Isoforms</h2> <p>The c-Jun N-terminal kinases consist of ten <a href="/facts/Protein_isoform/oWmzfg4l">isoforms</a> derived from three genes: <a href="/facts/MAPK8/fbUM7qyf">JNK1</a> (four isoforms), <a href="/facts/Mitogen-activated_protein_kinase_9/tJBv9rC6">JNK2</a> (four isoforms) and <a href="/facts/MAPK10/NHFwjuqA">JNK3</a> (two isoforms).<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> Each gene is expressed as either 46 kDa or 55 kDa protein kinases, depending upon how the 3' coding region of the corresponding mRNA is processed. There have been no functional differences documented between the 46 kDa and the 55 kDa isoform, however, a second form of alternative splicing occurs within transcripts of JNK1 and JNK2, yielding JNK1-α, JNK2-α and JNK1-β and JNK2-β. Differences in interactions with protein substrates arise because of the mutually exclusive utilization of two <a href="/facts/Exon/8KWJtLuN">exons</a> within the kinase domain.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p><p>c-Jun N-terminal kinase isoforms have the following tissue distribution: </p> <ul><li><a href="/facts/MAPK8/fbUM7qyf">JNK1</a> and <a href="/facts/Mitogen-activated_protein_kinase_9/tJBv9rC6">JNK2</a> are found in all cells and tissues.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a></li> <li><a href="/facts/MAPK10/NHFwjuqA">JNK3</a> is found mainly in the brain, but is also found in the heart and the testes.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a></li></ul> <h2 id="function">Function</h2> <p>Inflammatory signals, changes in levels of <a href="/facts/Reactive_oxygen_species/GpwSRugH">reactive oxygen species</a>, ultraviolet radiation, protein synthesis inhibitors, and a variety of stress stimuli can activate JNK. One way this activation may occur is through disruption of the conformation of sensitive <a href="/facts/Phosphatase/LBJs1fXx">protein phosphatase</a> enzymes; specific phosphatases normally inhibit the activity of JNK itself and the activity of proteins linked to JNK activation.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p><p>JNKs can associate with <a href="/facts/Scaffold_protein/uKnJq24r">scaffold proteins</a> JNK interacting proteins (JIP) as well as their upstream kinases <a href="/facts/MAP2K4/LCE6jH2W">JNKK1</a> and <a href="/facts/MAP2K7/99JIHCKC">JNKK2</a> following their activation. </p><p>JNK, by phosphorylation, modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus. Downstream molecules that are activated by JNK include <a href="/facts/C-jun/Cbvb15yT">c-Jun</a>, <a href="/facts/Activating_transcription_factor_2/kvue3G39">ATF2</a>, <a href="/facts/ELK1/wdJJr4sH">ELK1</a>, <a href="/facts/Mothers_against_decapentaplegic_homolog_4/cgvz1vKP">SMAD4</a>, <a href="/facts/P53/YEGULLgM">p53</a> and <a href="/facts/HSF1/7QTPE6t9">HSF1</a>. The downstream molecules that are inhibited by JNK activation include <a href="/facts/NFATC3/75btB1JN">NFAT4</a>, <a href="/facts/NFATC1/vGPcPkf2">NFATC1</a> and <a href="/facts/STAT3/8NS3V4Mj">STAT3</a>. By activating and inhibiting other small molecules in this way, JNK activity regulates several important cellular functions including cell growth, differentiation, survival and apoptosis. </p><p>JNK1 is involved in <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a>, <a href="/facts/Neurodegeneration/HTDrVEqc">neurodegeneration</a>, cell differentiation and proliferation, inflammatory conditions and <a href="/facts/Cytokine/SdWpWABH">cytokine</a> production mediated by AP-1 (<a href="/facts/AP-1_transcription_factor/jryICv0m">activation protein 1</a>) such as <a href="/facts/RANTES/bfcYCrNH">RANTES</a>, <a href="/facts/Interleukin_8/evhcrTme">IL-8</a> and <a href="/facts/GM-CSF/U15M21QE">GM-CSF</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Recently, JNK1 has been found to regulate <a href="/facts/C-jun/Cbvb15yT">Jun</a> <a href="/facts/Protein_turnover/A0N0TMK2">protein turnover</a> by <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> and activation of the <a href="/facts/Ubiquitin_ligase/8xmNaWW3">ubiquitin ligase</a> <a href="/facts/ITCH_(biology)/eSh9v0h5">Itch</a>. </p><p><a href="/facts/Neurotrophin/NwuESuUa">Neurotrophin</a> binding to <a href="/facts/Low-affinity_nerve_growth_factor_receptor/Pm9SMrH3">p75NTR</a> activates a JNK signaling pathway causing apoptosis of developing neurons. JNK, through a series of intermediates, activates <a href="/facts/P53/YEGULLgM">p53</a> and p53 activates <a href="/facts/Bcl-2-associated_X_protein/jfvo8zca">Bax</a> which initiates apoptosis. <a href="/facts/Tropomyosin_receptor_kinase_A/N4hKvo9G">TrkA</a> can prevent p75NTR-mediated JNK pathway apoptosis.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> JNK can directly phosphorylate Bim-EL, a splicing <a href="/facts/Protein_isoform/oWmzfg4l">isoform</a> of <a href="/facts/Bcl-2/I34R1guW">Bcl-2 interacting mediator of cell death (Bim)</a>, which activates Bim-EL apoptotic activity. JNK activation is required for apoptosis but <a href="/facts/C-jun/Cbvb15yT">c-jun</a>, a protein involved in the JNK pathway, is not always required.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="roles-in-dna-repair">Roles in DNA repair</h2> <p>The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow repair of double-strand breaks in DNA, the chromatin must be remodeled.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> Chromatin relaxation occurs rapidly at the site of a DNA damage.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> In one of the earliest steps, JNK phosphorylates <a href="/facts/SIRT6/pI41InaS">SIRT6</a> on <a href="/facts/Serine/4duVl30B">serine</a> 10 in response to double-strand breaks (DSBs) or other DNA damage, and this step is required for efficient repair of DSBs.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> Phosphorylation of SIRT6 on S10 facilitates the mobilization of SIRT6 to DNA damage sites, where SIRT6 then recruits and mono-phosphorylates poly (ADP-ribose) polymerase 1 (<a href="/facts/PARP1/ct3W2NDG">PARP1</a>) at DNA break sites.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> Half maximum accumulation of PARP1 occurs within 1.6 seconds after the damage occurs.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> The chromatin remodeler <a href="/facts/CHD1L/XbP6rUBe">Alc1</a> quickly attaches to the product of PARP1 action, a poly-ADP ribose chain,<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> allowing half of the maximum chromatin relaxation, presumably due to action of Alc1, by 10 seconds.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> This allows recruitment of the DNA repair enzyme <a href="/facts/MRE11A/HL8z8XmK">MRE11</a>, to initiate DNA repair, within 13 seconds.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p><p>Removal of UV-induced DNA <a href="/facts/Pyrimidine_dimer/pHkppBcM">photoproducts</a>, during <a href="/facts/Nucleotide_excision_repair/C8HYoS1M">transcription coupled nucleotide excision repair (TC-NER)</a>, depends on JNK phosphorylation of <a href="/facts/DGCR8/pvTEXmDh">DGCR8</a> on <a href="/facts/Serine/4duVl30B">serine</a> 153.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> While DGCR8 is usually known to function in microRNA biogenesis, the microRNA-generating activity of DGCR8 is not required for DGCR8-dependent removal of UV-induced photoproducts.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> <a href="/facts/Nucleotide_excision_repair/C8HYoS1M">Nucleotide excision repair</a> is also needed for repair of oxidative DNA damage due to <a href="/facts/Hydrogen_peroxide/vju6HBIc">hydrogen peroxide</a> (H2O2), and DGCR8 depleted cells are sensitive to H2O2.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p> <h2 id="in-aging">In aging</h2> <p>In <i><a href="/facts/Drosophila_melanogaster/KtnHVCcB">Drosophila</a></i>, flies with mutations that augment JNK signaling accumulate less oxidative damage and live dramatically longer than wild-type flies.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p><p>In the tiny roundworm <i><a href="/facts/Caenorhabditis_elegans/XJVJzPn2">Caenorhabditis elegans</a></i>, loss-of-function mutants of JNK-1 have a decreased life span, while amplified expression of wild-type JNK-1 extends life span by 40%.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> Worms with overexpressed JNK-1 also have significantly increased resistance to oxidative stress and other stresses.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li> Biology portal</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=JNK+Mitogen-Activated+Protein+Kinases">JNK+Mitogen-Activated+Protein+Kinases</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li><a href="https://web.archive.org/web/20110727235656/http://beaker.sanfordburnham.org/?p=1026">Getting a Handle on Cellular JNK</a> (from Beaker Blog)</li> <li><a href="http://www.mapkinases.eu">MAP Kinase Resource</a> <a href="https://web.archive.org/web/20210415072533/http://www.mapkinases.eu/">Archived</a> 2021-04-15 at the <a href="/facts/Wayback_Machine/nmQ3a6JC">Wayback Machine</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Ip YT, Davis RJ (April 1998). "Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development". Curr. Opin. Cell Biol. 10 (2): 205–19. doi:10.1016/S0955-0674(98)80143-9. PMID 9561845. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Waetzig V, Herdegen T (2005). "Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage". Br. J. Pharmacol. 26 (9): 455–61. doi:10.1016/j.tips.2005.07.006. PMID 16054242. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Ip YT, Davis RJ (April 1998). "Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development". Curr. Opin. Cell Biol. 10 (2): 205–19. doi:10.1016/S0955-0674(98)80143-9. 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The protein products of jnk1 and jnk2 are believed to be expressed in every cell and tissue type, whereas the JNK3 protein is found primarily in brain and to a lesser extent in heart and testis <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832829" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832829</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Vlahopoulos S, Zoumpourlis VC (August 2004). "JNK: a key modulator of intracellular signaling". Biochemistry Mosc. 69 (8): 844–54. doi:10.1023/B:BIRY.0000040215.02460.45. PMID 15377263. S2CID 39149612. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Oltmanns U, Issa R, Sukkar MB, John M, Chung KF (July 2003). "Role of c-jun N-terminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells". Br. J. 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The Journal of Neuroscience. 24 (40): 8762–8770. doi:10.1523/JNEUROSCI.2953-04.2004. PMC 6729963. PMID 15470142. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729963" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729963</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Liu B, Yip RK, Zhou Z (2012). "Chromatin remodeling, DNA damage repair and aging". Curr. Genomics. 13 (7): 533–47. doi:10.2174/138920212803251373. PMC 3468886. PMID 23633913. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468886" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468886</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Sellou H, Lebeaupin T, Chapuis C, Smith R, Hegele A, Singh HR, Kozlowski M, Bultmann S, Ladurner AG, Timinszky G, Huet S (2016). "The poly(ADP-ribose)-dependent chromatin remodeler Alc1 induces local chromatin relaxation upon DNA damage". Mol. Biol. 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Bibcode:2005PNAS..102.4494O. doi:10.1073/pnas.0500749102. PMC 555525. PMID 15767565. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC555525" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC555525</a> <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> <li id="fn:24"><p>Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA (2005). "JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16". Proc. Natl. Acad. Sci. U.S.A. 102 (12): 4494–9. Bibcode:2005PNAS..102.4494O. doi:10.1073/pnas.0500749102. PMC 555525. PMID 15767565. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC555525" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC555525</a> <a href="#fnref:24" class="footnote-back-ref">↩</a></p></li> </ol>