mitogen activated protein kinase 8


Summary: A c-jun amino-terminal kinase that is activated by environmental stress and pro-inflammatory cytokines. Several isoforms of the protein with molecular sizes of 43 and 48 KD exist due to multiple ALTERNATIVE SPLICING.

Top Publications

  1. Das M, Jiang F, Sluss H, Zhang C, Shokat K, Flavell R, et al. Suppression of p53-dependent senescence by the JNK signal transduction pathway. Proc Natl Acad Sci U S A. 2007;104:15759-64 pubmed
    ..These data demonstrate that JNK can act as a negative regulator of the p53 tumor suppressor. ..
  2. Witczak C, Hirshman M, Jessen N, Fujii N, Seifert M, Brandauer J, et al. JNK1 deficiency does not enhance muscle glucose metabolism in lean mice. Biochem Biophys Res Commun. 2006;350:1063-8 pubmed
    ..This study is the first to directly demonstrate that enhanced skeletal muscle glucose metabolism does not underlie the beneficial effects of JNK1 deficiency in lean mice. ..
  3. Yang R, Wilcox D, Haasch D, Jung P, Nguyen P, Voorbach M, et al. Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice. J Biol Chem. 2007;282:22765-74 pubmed
    ..Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice. ..
  4. Hsu L, Schultz L, Mattison J, Lin Y, Chang N. Cloning and characterization of a small-size peptide Zfra that regulates the cytotoxic function of tumor necrosis factor by interacting with JNK1. Biochem Biophys Res Commun. 2005;327:415-23 pubmed
    ..While JNK1 is a downstream effector of the TNF signaling, Zfra regulation of the TNF cytotoxic function is likely due to its interaction, in part, with JNK1. ..
  5. Sabapathy K, Hochedlinger K, Nam S, Bauer A, Karin M, Wagner E. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell. 2004;15:713-25 pubmed
    ..In contrast, JNK1 becomes the major c-Jun interacting kinase after cell stimulation. These data provide mechanistic insights into the distinct roles of different JNK isoforms. ..
  6. Björkblom B, Vainio J, Hongisto V, Herdegen T, Courtney M, Coffey E. All JNKs can kill, but nuclear localization is critical for neuronal death. J Biol Chem. 2008;283:19704-13 pubmed publisher
    ..Thus any one of the three JNKs is capable of mediating apoptosis and inhibition of nuclear JNK is protective. ..
  7. Singh R, Wang Y, Xiang Y, Tanaka K, Gaarde W, Czaja M. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology. 2009;49:87-96 pubmed publisher
  8. Yoo J, Park S, Lee Y. Pretreatment of docetaxel enhances TRAIL-mediated apoptosis in prostate cancer cells. J Cell Biochem. 2008;104:1636-46 pubmed publisher
    ..The results of our study show that pretreatment of docetaxel is able to enhance the apoptosis produced by TRAIL in prostate cancer cells, especially in hormone-refractory prostate cancer (HRPC). ..
  9. Ricci R, Sumara G, Sumara I, Rozenberg I, Kurrer M, Akhmedov A, et al. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science. 2004;306:1558-61 pubmed
    ..Thus, JNK2-dependent phosphorylation of SR-A promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis. ..

More Information


  1. Liu J, Minemoto Y, Lin A. c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis. Mol Cell Biol. 2004;24:10844-56 pubmed
    ..TNF-alpha-induced apoptosis was also suppressed in Jnk1 null fibroblasts but increased in Jnk2 null cells. Thus, our results provide a molecular mechanism underlying the different biological functions of JNK isoforms. ..
  2. Aderca I, Moser C, Veerasamy M, Bani Hani A, Bonilla Guerrero R, Ahmed K, et al. The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX. J Hepatol. 2008;49:373-83 pubmed publisher
    ..WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition. ..
  3. Tuncman G, Hirosumi J, Solinas G, Chang L, Karin M, Hotamisligil G. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc Natl Acad Sci U S A. 2006;103:10741-6 pubmed
    ..These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms. ..
  4. Chang Q, Zhang Y, Beezhold K, Bhatia D, Zhao H, Chen J, et al. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J Hepatol. 2009;50:323-33 pubmed publisher
    ..These results, thus, suggest that JNK1 plays important roles in the development of human HCC partially through the epigenetic mechanisms. ..
  5. Koyama T, Mikami T, Koyama T, Imakiire A, Yamamoto K, Toyota H, et al. Apoptosis induced by chemotherapeutic agents involves c-Jun N-terminal kinase activation in sarcoma cell lines. J Orthop Res. 2006;24:1153-62 pubmed
    ..Apoptosis was determined by flow cytometry using annexin-V Cy5. Collectively, our results indicate that JNK activation is involved in apoptotic cell death in sarcoma cell lines following stimulation with CDDP or DXR. ..
  6. Gallagher E, Gao M, Liu Y, Karin M. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. Proc Natl Acad Sci U S A. 2006;103:1717-22 pubmed
  7. Das M, Sabio G, Jiang F, Rincon M, Flavell R, Davis R. Induction of hepatitis by JNK-mediated expression of TNF-alpha. Cell. 2009;136:249-60 pubmed publisher
    ..These observations confirm a role for JNK in the development of hepatitis but identify hematopoietic cells as the site of the essential function of JNK. ..
  8. Hui L, Zatloukal K, Scheuch H, Stepniak E, Wagner E. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest. 2008;118:3943-53 pubmed publisher
    ..These findings provide a mechanistic link between JNK activity and liver cell proliferation via p21 and c-Myc and suggest JNK targeting can be considered as a new therapeutic approach for HCC treatment. ..
  9. Zhong S, Fromm J, Johnson D. TBP is differentially regulated by c-Jun N-terminal kinase 1 (JNK1) and JNK2 through Elk-1, controlling c-Jun expression and cell proliferation. Mol Cell Biol. 2007;27:54-64 pubmed
    ..These studies uncovered several new molecular events that distinguish the functions of JNK1 and JNK2 that are critical for their regulation of cellular proliferation. ..
  10. Sakurai T, Maeda S, Chang L, Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A. 2006;103:10544-51 pubmed
  11. Chen F, Castranova V. Beyond apoptosis of JNK1 in liver cancer. Cell Cycle. 2009;8:1145-7 pubmed
    ..Accordingly, we believe that targeting JNK1 is not only mechanistically sound but also clinically feasible for the treatment of HCC. ..
  12. Chen X, Trivedi P, Ge B, Krzewski K, Strominger J. Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity. Proc Natl Acad Sci U S A. 2007;104:6329-34 pubmed
    ..By contrast, CD2, DNAM-1, and beta(1)-integrin crosslinking do not activate either pathway; they may be costimulatory molecules or have another function in the synapse...
  13. Björkblom B, Ostman N, Hongisto V, Komarovski V, Filén J, Nyman T, et al. Constitutively active cytoplasmic c-Jun N-terminal kinase 1 is a dominant regulator of dendritic architecture: role of microtubule-associated protein 2 as an effector. J Neurosci. 2005;25:6350-61 pubmed
    ..Together, these data suggest that JNK phosphorylation of MAP2 plays an important role in defining dendritic architecture in the brain. ..
  14. Ozcan U, Cao Q, Yilmaz E, Lee A, Iwakoshi N, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457-61 pubmed
    ..Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases. ..
  15. Kaneto H, Nakatani Y, Miyatsuka T, Kawamori D, Matsuoka T, Matsuhisa M, et al. Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med. 2004;10:1128-32 pubmed
    ..These data indicate that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK-inhibitory peptide may have promise as a new therapeutic agent for diabetes. ..
  16. Chang L, Jones Y, Ellisman M, Goldstein L, Karin M. JNK1 is required for maintenance of neuronal microtubules and controls phosphorylation of microtubule-associated proteins. Dev Cell. 2003;4:521-33 pubmed
    ..These results suggest that JNK1 is required for maintaining the cytoskeletal integrity of neuronal cells and is a critical regulator of MAP activity and MT assembly. ..
  17. Huang C, Rajfur Z, Borchers C, Schaller M, Jacobson K. JNK phosphorylates paxillin and regulates cell migration. Nature. 2003;424:219-23 pubmed
    ..Expression of Pax(S178A) also inhibited the migration of two other cell lines. Thus, phosphorylation of paxillin by JNK seems essential for maintaining the labile adhesions required for rapid cell migration. ..
  18. Morse D, Pischke S, Zhou Z, Davis R, Flavell R, Loop T, et al. Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J Biol Chem. 2003;278:36993-8 pubmed
    ..For the first time, the effect of CO is shown to be mediated via the JNK signaling pathway and the transcription factor AP-1. ..
  19. Song J, Lee Y. Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization. J Biol Chem. 2003;278:47245-52 pubmed
    ..The relocalized Daxx may play an important role in glucose deprivation-induced ASK1 oligomerization. ..
  20. Zhang S, Liu J, Dragunow M, Cooper G. Fibrillogenic amylin evokes islet beta-cell apoptosis through linked activation of a caspase cascade and JNK1. J Biol Chem. 2003;278:52810-9 pubmed
    ..Fibrillogenic amylin can evoke a JNK1-mediated apoptotic pathway, which is partially dependent and partially independent of caspase-8, and in which caspase-3 acts as a common downstream effector. ..
  21. Song J, Lee Y. Effect of glucose concentration on activation of the ASK1-SEK1-JNK1 signal transduction pathway. J Cell Biochem. 2003;89:653-62 pubmed
    ..01 mm. ..
  22. Fujii N, Boppart M, Dufresne S, Crowley P, Jozsi A, Sakamoto K, et al. Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity. Am J Physiol Cell Physiol. 2004;287:C200-8 pubmed
    ..JNK activation is unlikely to be the major mechanism by which contractile activity increases glycogen synthase activity in skeletal muscle. ..
  23. Sánchez Galán E, Gómez Hernández A, Vidal C, Martin Ventura J, Blanco Colio L, Munoz Garcia B, et al. Leukotriene B4 enhances the activity of nuclear factor-kappaB pathway through BLT1 and BLT2 receptors in atherosclerosis. Cardiovasc Res. 2009;81:216-25 pubmed publisher
    ..The blockade of this pathway could be a novel and potential therapeutic target in atherothrombosis. ..
  24. Katagiri C, Negishi K, Hibino T. c-JUN N-terminal kinase-1 (JNK1) but not JNK2 or JNK3 is involved in UV signal transduction in human epidermis. J Dermatol Sci. 2006;43:171-9 pubmed
    ..In addition, recombinant SCCA1 suppressed kinase activity of JNK1 but did not affect JNK2 or JNK3 kinase activity. JNK1 is associated with UV signal transduction in human epidermis and SCCA1 is a suppressor of this process. ..
  25. Lalioti V, Vergarajauregui S, Tsuchiya Y, Hernandez Tiedra S, Sandoval I. Daxx functions as a scaffold of a protein assembly constituted by GLUT4, JNK1 and KIF5B. J Cell Physiol. 2009;218:416-26 pubmed publisher
    ..Depletion of Daxx in 3T3-L1 adipocytes provokes the partial translocation of the GLUT4 retained in the GLUT4 storage compartment to endosomes. ..
  26. Xia M, Ling W, Zhu H, Ma J, Wang Q, Hou M, et al. Anthocyanin attenuates CD40-mediated endothelial cell activation and apoptosis by inhibiting CD40-induced MAPK activation. Atherosclerosis. 2009;202:41-7 pubmed publisher
  27. Ho H, Moffat R, Patel R, Awah F, Baloue K, Crowe D. Embryoid body attachment to reconstituted basement membrane induces a genetic program of epithelial differentiation via jun N-terminal kinase signaling. Stem Cell Res. 2010;5:144-56 pubmed publisher
    ..Inhibition of JNK signaling completely blocked epithelial differentiation in this model, revealing a key mechanism by which ES cells adopt epithelial characteristics via basement membrane attachment. ..
  28. Haddad J. Discordant tissue-specific expression of SAPK/MAPK(JNK)-related cofactors in hypoxia and hypoxia/reoxygenation in a model of anoxia-tolerance. Protein Pept Lett. 2007;14:373-80 pubmed
    ..Since these modules are involved with neuroprotection in Chrysemys picta bellii, the expression of MAPKs bears relative mechanisms of specific responses to hypoxia tolerance. ..
  29. Kuntzen C, Sonuc N, De Toni E, Opelz C, Mucha S, Gerbes A, et al. Inhibition of c-Jun-N-terminal-kinase sensitizes tumor cells to CD95-induced apoptosis and induces G2/M cell cycle arrest. Cancer Res. 2005;65:6780-8 pubmed
    ..We conclude that JNK inhibition has antitumor activity by inducing growth arrest and enhancing CD95-mediated apoptosis by a transcription-independent mechanism. ..
  30. Mann K, Davison K, Colombo M, Colosimo A, Diaz Z, Padovani A, et al. Antimony trioxide-induced apoptosis is dependent on SEK1/JNK signaling. Toxicol Lett. 2006;160:158-70 pubmed
    ..These data suggest roles for ROS and the SEK1/JNK pathway in the cytotoxicity associated with Sb(2)O(3) exposure. ..
  31. Komiya K, Uchida T, Ueno T, Koike M, Abe H, Hirose T, et al. Free fatty acids stimulate autophagy in pancreatic ?-cells via JNK pathway. Biochem Biophys Res Commun. 2010;401:561-7 pubmed publisher
    ..Considered together, our study suggested that FFA stimulated functional autophagy possibly through the PKR-JNK1 pathway independent of ER or oxidative stress. ..
  32. Kim T, Wayne Leitner J, Adochio R, Draznin B. Knockdown of JNK rescues 3T3-L1 adipocytes from insulin resistance induced by mitochondrial dysfunction. Biochem Biophys Res Commun. 2009;378:772-6 pubmed publisher
    ..Thus, FCCP-induced mitochondrial dysfunction may cause insulin resistance that is ameliorated by reduction of JNK1 expression. ..
  33. D Alessio A, Kluger M, Li J, Al Lamki R, Bradley J, Pober J. Targeting of tumor necrosis factor receptor 1 to low density plasma membrane domains in human endothelial cells. J Biol Chem. 2010;285:23868-79 pubmed publisher
    ..Furthermore, both NF-kappaB and SAPK activation appear independent of both TNFR1 localization to low density membrane domains and to TNF-induced receptor internalization. ..
  34. Liu J, Lin A. Wiring the cell signaling circuitry by the NF-kappa B and JNK1 crosstalk and its applications in human diseases. Oncogene. 2007;26:3267-78 pubmed
    ..Understanding the wiring of the cell signaling circuitry may hold the key for cell signaling-based therapy of human diseases. ..
  35. Fu P, Liang G, Khot S, Phan R, Bach L. Cross-talk between MAP kinase pathways is involved in IGF-independent, IGFBP-6-induced Rh30 rhabdomyosarcoma cell migration. J Cell Physiol. 2010;224:636-43 pubmed publisher
    ..Understanding these disparate actions of IGFBP-6 may lead to the development of novel cancer therapeutics. ..
  36. Takahashi H, Ogata H, Nishigaki R, Broide D, Karin M. Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell. 2010;17:89-97 pubmed publisher
    ..Tumor promotion is due to induction of inflammation that results in enhanced pneumocyte proliferation and is abrogated by IKKbeta ablation in myeloid cells or inactivation of JNK1. ..
  37. Bashan N, Dorfman K, Tarnovscki T, Harman Boehm I, Liberty I, Bluher M, et al. Mitogen-activated protein kinases, inhibitory-kappaB kinase, and insulin signaling in human omental versus subcutaneous adipose tissue in obesity. Endocrinology. 2007;148:2955-62 pubmed
    ..Increased expression of stress-activated kinases and IKK and their phosphorylated forms in omental fat occurs in obesity, potentially contributing to differential roles of omental and sc fat in the pathophysiology of obesity. ..
  38. Park H, Mo J, Choi E. Nitric oxide inhibits an interaction between JNK1 and c-Jun through nitrosylation. Biochem Biophys Res Commun. 2006;351:281-6 pubmed
    ..Collectively, our results suggest that the inhibition of the interaction between JNK and c-Jun may be an integral part of the mechanism underlying the negative regulation of the JNK signaling pathway by NO. ..
  39. Ki S, Choi M, Lee C, Kim S. Galpha12 specifically regulates COX-2 induction by sphingosine 1-phosphate. Role for JNK-dependent ubiquitination and degradation of IkappaBalpha. J Biol Chem. 2007;282:1938-47 pubmed
  40. Ogawa E, Okuyama R, Egawa T, Nagoshi H, Obinata M, Tagami H, et al. p63/p51-induced onset of keratinocyte differentiation via the c-Jun N-terminal kinase pathway is counteracted by keratinocyte growth factor. J Biol Chem. 2008;283:34241-9 pubmed publisher
    ..These data may provide mechanistic explanations for the pathological features of skin diseases, including psoriasis. ..
  41. Haag P, Viktorsson K, Lindberg M, Kanter L, Lewensohn R, Stenke L. Deficient activation of Bak and Bax confers resistance to gemtuzumab ozogamicin-induced apoptotic cell death in AML. Exp Hematol. 2009;37:755-66 pubmed publisher
    ..Our novel data on GO-induced proapoptotic activation of Bax, Bak, and stress-activated protein kinase indicate an important role for these signal proteins in the regulation of GO sensitivity in AML. ..
  42. Han J, Crowe D. Jun amino-terminal kinase 1 activation promotes cell survival in ErbB2-positive breast cancer. Anticancer Res. 2010;30:3407-12 pubmed
    ..JNK1 was preferentially activated in human breast cancer tissue overexpressing Her2/neu. JNK1 promotes cell survival in Her2/neu-positive breast cancer. ..
  43. Caron R, Yacoub A, Mitchell C, Zhu X, Hong Y, Sasazuki T, et al. Radiation-stimulated ERK1/2 and JNK1/2 signaling can promote cell cycle progression in human colon cancer cells. Cell Cycle. 2005;4:456-64 pubmed
    ..In HCT116 cells H-RAS V12 promotes hMDM2 expression after radiation exposure which correlates with reduced p53 expression and increased cell survival. ..
  44. Schmidt M, Budirahardja Y, Klompmaker R, Medema R. Ablation of the spindle assembly checkpoint by a compound targeting Mps1. EMBO Rep. 2005;6:866-72 pubmed
    ..Remarkably, primary human cells are largely resistant to the checkpoint-inactivating action of SP600125, suggesting the existence of Mps1-independent checkpoint pathways that are compromised in tumour cells. ..
  45. Kawamori D, Kaneto H, Nakatani Y, Matsuoka T, Matsuhisa M, Hori M, et al. The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem. 2006;281:1091-8 pubmed
    ..Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway. ..
  46. Lee S, Moon G, Jung K, Kim W, Moon S. c-Jun N-terminal kinase 1 is required for cordycepin-mediated induction of G2/M cell-cycle arrest via p21WAF1 expression in human colon cancer cells. Food Chem Toxicol. 2010;48:277-83 pubmed publisher
    ..Together, these results suggest a critical role for JNK1 activation in cordycepin-induced inhibition of cell growth and G2/M-phase arrest in human colon cancer cells. ..
  47. Wang J, Zhang W, Zhang Y, Chen Y, Zou B, Jiang B, et al. c-Jun N-terminal kinase (JNK1) upregulates XIAP-associated factor 1 (XAF1) through interferon regulatory factor 1 (IRF-1) in gastrointestinal cancer. Carcinogenesis. 2009;30:222-9 pubmed publisher
    ..The linkage of JNK1, IRF-1 and XAF1 in the same signal pathway may unravel a novel mechanism in regulation of apoptosis and differentiation of GI cancers. ..
  48. Ono R, Matsuoka J, Yamatsuji T, Naomoto Y, Tanaka N, Matsui H, et al. M-RIP, a novel target of JNK signaling and a requirement for human cancer cell invasion. Int J Mol Med. 2008;22:199-203 pubmed
    ..Thus, a functional analysis of JNK1 and M-RIP with RNA interference reveals a critical role for this cascade in the invasive behavior of cancer cells. ..
  49. Unger E, Piper M, Olofsson L, Xu A. Functional role of c-Jun-N-terminal kinase in feeding regulation. Endocrinology. 2010;151:671-82 pubmed publisher
    ..Thus, JNK may integrate diverse metabolic signals and differentially regulate feeding under distinct physiological conditions. ..
  50. Bell C, Larivière N, Watson P, Watson A. Mitogen-activated protein kinase (MAPK) pathways mediate embryonic responses to culture medium osmolarity by regulating Aquaporin 3 and 9 expression and localization, as well as embryonic apoptosis. Hum Reprod. 2009;24:1373-86 pubmed publisher
    ..MAPK14/11 activation is a component of the rapid adaptive stress response mechanism that includes the effects of AQP mRNA expression and protein localization, whereas the MAPK8 pathway is a regulator of apoptosis. ..
  51. Yi P, Qiu M. 3D-QSAR and docking studies of aminopyridine carboxamide inhibitors of c-Jun N-terminal kinase-1. Eur J Med Chem. 2008;43:604-13 pubmed
    ..The analyses may be used to design more potent aminopyridine carboxamides and predict their activity prior to synthesis. ..
  52. Kim M, Murakami A, Kawabata K, Ohigashi H. (-)-Epigallocatechin-3-gallate promotes pro-matrix metalloproteinase-7 production via activation of the JNK1/2 pathway in HT-29 human colorectal cancer cells. Carcinogenesis. 2005;26:1553-62 pubmed
    ..Our results suggest that some green tea catechins induce pro-MMP-7 production via O2- production and the activation of JNK1/2, c-JUN, c-FOS and AP-1 in HT-29 cells. ..
  53. Soh J, Kazi J, Li H, Thompson W, Weinstein I. Celecoxib-induced growth inhibition in SW480 colon cancer cells is associated with activation of protein kinase G. Mol Carcinog. 2008;47:519-25 pubmed publisher