MAPK8 explained

Mitogen-activated protein kinase 8 (also known as JNK1) is a ubiquitous enzyme that in humans is encoded by the MAPK8 gene.^{[1] [2]}

Function

The protein encoded by this gene is a member of the MAP kinase and JNK family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various cell stimuli, and targets specific transcription factors, and thus mediates immediate-early gene expression in response to cell stimuli. The activation of this kinase by tumor-necrosis factor alpha (TNF-alpha) is found to be required for TNF-alpha-induced apoptosis. This kinase is also involved in UV radiation-induced apoptosis, which is thought to be related to the cytochrome c-mediated cell death pathway. Studies of the mouse counterpart of this gene suggested that this kinase play a key role in T cell proliferation, apoptosis and differentiation. Four alternately spliced transcript variants encoding distinct isoforms have been reported.^[3] MAPK8 contains multiple amino acid sites that are phosphorylated and ubiquitinated.^[4]

Interactions

MAPK8 has been shown to interact with:

• Activating transcription factor 2,^{[5] [6] [7] [8]}
• C-jun,^{[8] [9] [10] [11] [12] [13]}
• CRK,^[14]
• DUSP10,^[15]
• DUSP1,^[16]
• GSTP1,^[17]
• IRS1,^{[18] [19]}
• ITCH, ^{[20] [21]}
• MAP2K4,^{[7] [8] [22] [23]}
• MAP2K7,^{[8] [24]}
• MAP3K1^[25]
• MAP3K2,^[24]
• MAPK8IP1,^{[26] [27]}
• MAPK8IP3,^{[28] [29]}
• Myc,^[30]
• REL,^[31]
• SH3BP5,^[32] and
• SPIB.^[33]

Further reading

• Lin, A . The JNK Signaling Pathway (Molecular Biology Intelligence Unit) . Landes Bioscience . 1 . 1–97 . 2006 . 978-1587061202.
• Davis RJ . Signal transduction by the JNK group of MAP kinases . Cell . 103 . 2 . 239–52 . 2000 . 11057897 . 10.1016/S0092-8674(00)00116-1 . 343677 . free .
• Liu J, Lin A . Wiring the cell signaling circuitry by the NF-kappa B and JNK1 crosstalk and its applications in human diseases . Oncogene . 26 . 22 . 3267–78 . 2007 . 17496921 . 10.1038/sj.onc.1210417 . 28428831 . free .

External links

• MAP Kinase Resource .

Notes and References

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2. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Dérijard B, Davis RJ . Selective interaction of JNK protein kinase isoforms with transcription factors . EMBO J. . 15 . 11 . 2760–70 . July 1996 . 8654373 . 450211 . 10.1002/j.1460-2075.1996.tb00636.x.
3. Web site: Entrez Gene: MAPK8 mitogen-activated protein kinase 8.
4. Web site: JNK1 (human). 2020-10-28. www.phosphosite.org.
5. Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ . Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine . J. Biol. Chem. . 270 . 13 . 7420–6 . March 1995 . 7535770 . 10.1074/jbc.270.13.7420. free .
6. Fuchs SY, Xie B, Adler V, Fried VA, Davis RJ, Ronai Z . c-Jun NH2-terminal kinases target the ubiquitination of their associated transcription factors . J. Biol. Chem. . 272 . 51 . 32163–8 . December 1997 . 9405416 . 10.1074/jbc.272.51.32163. free.
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8. Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ . Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase . Proc. Natl. Acad. Sci. U.S.A. . 94 . 14 . 7337–42 . July 1997 . 9207092 . 23822 . 10.1073/pnas.94.14.7337. 1997PNAS...94.7337T . free .
9. Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K . Richard Gaynor . Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling . EMBO J. . 22 . 23 . 6277–88 . December 2003 . 14633987 . 291846 . 10.1093/emboj/cdg605 .
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12. Tada K, Okazaki T, Sakon S, Kobarai T, Kurosawa K, Yamaoka S, Hashimoto H, Mak TW, Yagita H, Okumura K, Yeh WC, Nakano H . Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death . J. Biol. Chem. . 276 . 39 . 36530–4 . September 2001 . 11479302 . 10.1074/jbc.M104837200 . free .
13. Cano E, Hazzalin CA, Kardalinou E, Buckle RS, Mahadevan LC . Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction . J. Cell Sci. . 108 . 11. 3599–609 . November 1995 . 10.1242/jcs.108.11.3599 . 8586671 .
14. Girardin SE, Yaniv M . A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation . EMBO J. . 20 . 13 . 3437–46 . July 2001 . 11432831 . 125507 . 10.1093/emboj/20.13.3437 .
15. Tanoue T, Moriguchi T, Nishida E . Molecular cloning and characterization of a novel dual specificity phosphatase, MKP-5 . J. Biol. Chem. . 274 . 28 . 19949–56 . July 1999 . 10391943 . 10.1074/jbc.274.28.19949. free .
16. Slack DN, Seternes OM, Gabrielsen M, Keyse SM . Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1 . J. Biol. Chem. . 276 . 19 . 16491–500 . May 2001 . 11278799 . 10.1074/jbc.M010966200 . free .
17. Wang T, Arifoglu P, Ronai Z, Tew KD . Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus . J. Biol. Chem. . 276 . 24 . 20999–1003 . June 2001 . 11279197 . 10.1074/jbc.M101355200 . free .
18. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF . Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action . J. Biol. Chem. . 277 . 2 . 1531–7 . January 2002 . 11606564 . 10.1074/jbc.M101521200 . free .
19. Aguirre V, Uchida T, Yenush L, Davis R, White MF . The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307) . J. Biol. Chem. . 275 . 12 . 9047–54 . March 2000 . 10722755 . 10.1074/jbc.275.12.9047. free .
20. Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC, Karin M . Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch . Science . 306 . 5694 . 271–5 . October 2004 . 15358865 . 10.1126/science.1099414 . 2004Sci...306..271G . 31876966 . free .
21. Gallagher E, Gao M, Liu YC, Karin M . Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change . Proceedings of the National Academy of Sciences of the United States of America . 103 . 6 . 1717–22 . February 2006 . 16446428 . 1413664 . 10.1073/pnas.0510664103 . 2006PNAS..103.1717G . free .
22. Lee CM, Onésime D, Reddy CD, Dhanasekaran N, Reddy EP . JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors . Proc. Natl. Acad. Sci. U.S.A. . 99 . 22 . 14189–94 . October 2002 . 12391307 . 137859 . 10.1073/pnas.232310199 . 2002PNAS...9914189L . free .
23. Park HS, Kim MS, Huh SH, Park J, Chung J, Kang SS, Choi EJ . Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation . J. Biol. Chem. . 277 . 4 . 2573–8 . January 2002 . 11707464 . 10.1074/jbc.M110299200 . free .
24. Cheng J, Yang J, Xia Y, Karin M, Su B . Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation . Mol. Cell. Biol. . 20 . 7 . 2334–42 . April 2000 . 10713157 . 85399 . 10.1128/mcb.20.7.2334-2342.2000.
25. Xu S, Cobb MH . MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases . J. Biol. Chem. . 272 . 51 . 32056–60 . December 1997 . 9405400 . 10.1074/jbc.272.51.32056. free .
26. Elion EA . Routing MAP kinase cascades . Science . 281 . 5383 . 1625–6 . September 1998 . 9767029 . 10.1126/science.281.5383.1625. 28868990 .
27. Cai Y, Lechner MS, Nihalani D, Prindle MJ, Holzman LB, Dressler GR . Phosphorylation of Pax2 by the c-Jun N-terminal kinase and enhanced Pax2-dependent transcription activation . J. Biol. Chem. . 277 . 2 . 1217–22 . January 2002 . 11700324 . 10.1074/jbc.M109663200 . free .
28. Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto KI . JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway . Mol. Cell. Biol. . 19 . 11 . 7539–48 . November 1999 . 10523642 . 84763 . 10.1128/mcb.19.11.7539.
29. Kelkar N, Gupta S, Dickens M, Davis RJ . Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3 . Mol. Cell. Biol. . 20 . 3 . 1030–43 . February 2000 . 10629060 . 85220 . 10.1128/mcb.20.3.1030-1043.2000.
30. Noguchi K, Kitanaka C, Yamana H, Kokubu A, Mochizuki T, Kuchino Y . Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase . J. Biol. Chem. . 274 . 46 . 32580–7 . November 1999 . 10551811 . 10.1074/jbc.274.46.32580. free .
31. Meyer CF, Wang X, Chang C, Templeton D, Tan TH . Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating kappaB enhancer activation . J. Biol. Chem. . 271 . 15 . 8971–6 . April 1996 . 8621542 . 10.1074/jbc.271.15.8971. free .
32. Wiltshire C, Matsushita M, Tsukada S, Gillespie DA, May GH . A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab (SH3BP5), associates with mitochondria . Biochem. J. . 367 . Pt 3 . 577–85 . November 2002 . 12167088 . 1222945 . 10.1042/BJ20020553 .
33. Mao C, Ray-Gallet D, Tavitian A, Moreau-Gachelin F . Differential phosphorylations of Spi-B and Spi-1 transcription factors . Oncogene . 12 . 4 . 863–73 . February 1996 . 8632909 .