Genomes and Genes
mitogen activated protein kinase 9
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 48 and 54 KD exist due to multiple ALTERNATIVE SPLICING.
- Jaeschke A, Karasarides M, Ventura J, Ehrhardt A, Zhang C, Flavell R, et al. JNK2 is a positive regulator of the cJun transcription factor. Mol Cell. 2006;23:899-911 pubmed
- Kuan C, Yang D, Samanta Roy D, Davis R, Rakic P, Flavell R. The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron. 1999;22:667-76 pubmed..In contrast, increased apoptosis and caspase activation were found in the mutant forebrain, leading to precocious degeneration. These results suggest that Jnk1 and Jnk2 regulate region-specific apoptosis during early brain development. ..
- Hirosumi J, Tuncman G, Chang L, Gorgun C, Uysal K, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420:333-6 pubmed..Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics. ..
- Behrens A, Sabapathy K, Graef I, Cleary M, Crabtree G, Wagner E. Jun N-terminal kinase 2 modulates thymocyte apoptosis and T cell activation through c-Jun and nuclear factor of activated T cell (NF-AT). Proc Natl Acad Sci U S A. 2001;98:1769-74 pubmed..These results demonstrate that JNK signaling differentially uses c-Jun and NF-AT as molecular effectors during thymocyte apoptosis and T cell proliferation. ..
- Relógio A, Ben Dov C, Baum M, Ruggiu M, Gemund C, Benes V, et al. Alternative splicing microarrays reveal functional expression of neuron-specific regulators in Hodgkin lymphoma cells. J Biol Chem. 2005;280:4779-84 pubmed..This microarray design can help assess the role of alternative splicing in a variety of biological and medical problems and potentially serve as a diagnostic tool. ..
- Johnson G, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911-2 pubmed..The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity. ..
- Sabapathy K, Kallunki T, David J, Graef I, Karin M, Wagner E. c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation. J Exp Med. 2001;193:317-28 pubmed..Thus, JNK1 and JNK2 control similar functions during T cell maturation through differential targeting of distinct substrates. ..
- Davis R. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239-52 pubmed
- Yang Y, Bost F, Charbono W, Dean N, McKay R, Rhim J, et al. C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma. Clin Cancer Res. 2003;9:391-401 pubmed..The JNK pathway is a novel target in the treatment of prostate carcinoma. ..
- 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. ..
- Cui J, Han S, Wang C, Su W, Harshyne L, Holgado Madruga M, et al. c-Jun NH(2)-terminal kinase 2alpha2 promotes the tumorigenicity of human glioblastoma cells. Cancer Res. 2006;66:10024-31 pubmed..Our data provides evidence that JNK2alpha2 is the major active JNK isoform and is involved in the promotion of proliferation and growth of human glioblastoma tumors through specific activation of AKT and overexpression of eIF4E. ..
- Dickens M, Rogers J, Cavanagh J, Raitano A, Xia Z, Halpern J, et al. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science. 1997;277:693-6 pubmed..This analysis identifies JIP-1 as a specific inhibitor of the JNK signal transduction pathway and establishes protein targeting as a mechanism that regulates signaling by stress-activated MAP kinases. ..
- 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. ..
- Han Z, Chang L, Yamanishi Y, Karin M, Firestein G. Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis. Arthritis Rheum. 2002;46:818-23 pubmed..JNK-2 is a determinant of matrix degradation, but it has little effect on inflammation in arthritis. Complete inhibition of MMP expression and joint destruction will likely require combined JNK-1 and JNK-2 inhibition. ..
- Gomez M, Bosc L, Stevenson A, Wilkerson M, Hill Eubanks D, Nelson M. Constitutively elevated nuclear export activity opposes Ca2+-dependent NFATc3 nuclear accumulation in vascular smooth muscle: role of JNK2 and Crm-1. J Biol Chem. 2003;278:46847-53 pubmed
- David J, Sabapathy K, Hoffmann O, Idarraga M, Wagner E. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J Cell Sci. 2002;115:4317-25 pubmed..Thus, these data provide genetic evidence that JNK1 activation modulates osteoclastogenesis through both c-Jun-phosphorylation-dependent and -independent mechanisms. ..
- Coffey E, Smiciene G, Hongisto V, Cao J, Brecht S, Herdegen T, et al. c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons. J Neurosci. 2002;22:4335-45 pubmed..Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity. ..
- Conze D, Krahl T, Kennedy N, Weiss L, Lumsden J, Hess P, et al. c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. J Exp Med. 2002;195:811-23 pubmed..Thus, JNK1 and JNK2 play different roles during CD8(+) T cell activation and these roles differ from those in CD4(+) T cells. ..
- Kallunki T, Su B, Tsigelny I, Sluss H, Derijard B, Moore G, et al. JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 1994;8:2996-3007 pubmed..These results explain how two closely related MAP kinases can differ in their ability to recognize specific substrates and thereby elicit different biological responses. ..
- Ford J, Ahmed S, Allison S, Jiang M, Milner J. JNK2-dependent regulation of SIRT1 protein stability. Cell Cycle. 2008;7:3091-7 pubmed..Our observations identify a route for therapeutic modulation of SIRT1 protein levels in SIRT1-linked diseases including cancer, neurodegeneration and diabetes. ..
- 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. ..
- Yang D, Conze D, Whitmarsh A, Barrett T, Davis R, Rincon M, et al. Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2. Immunity. 1998;9:575-85 pubmed..The JNK MAP kinase signaling pathway, therefore, plays an important role in the balance of Th1 and Th2 immune responses. ..
- Sabapathy K, Hu Y, Kallunki T, Schreiber M, David J, Jochum W, et al. JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr Biol. 1999;9:116-25 pubmed..JNK2 is not required for activation-induced cell death of mature T cells. ..
- Chen N, Nomura M, She Q, Ma W, Bode A, Wang L, et al. Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. Cancer Res. 2001;61:3908-12 pubmed..These data suggest that JNK2 is critical in the tumor promotion process. ..
- Arbour N, Naniche D, Homann D, Davis R, Flavell R, Oldstone M. c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 signaling pathways have divergent roles in CD8(+) T cell-mediated antiviral immunity. J Exp Med. 2002;195:801-10 pubmed..JNK1 is involved in survival of activated T cells during immune responses, and JNK2 plays a role in control of CD8(+) T cell expansion in vivo. ..
- Chen P, O Neal J, Ebelt N, Cantrell M, Mitra S, Nasrazadani A, et al. Jnk2 effects on tumor development, genetic instability and replicative stress in an oncogene-driven mouse mammary tumor model. PLoS ONE. 2010;5:e10443 pubmed publisher..Together, these data support that JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms. ..
- Kyriakis J, Banerjee P, Nikolakaki E, Dai T, Rubie E, Ahmad M, et al. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994;369:156-60 pubmed..9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun. ..
- Gupta S, Barrett T, Whitmarsh A, Cavanagh J, Sluss H, Derijard B, et al. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996;15:2760-70 pubmed..Individual members of the JNK group may therefore selectively target specific transcription factors in vivo. ..
- Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, et al. 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. 1999;19:7539-48 pubmed..These results suggest that JSAP1 functions as a scaffold protein in the JNK3 cascade. We also discuss a scaffolding role for JSAP1 in the JNK1 and JNK2 cascades. ..
- Ule J, Jensen K, Ruggiu M, Mele A, Ule A, Darnell R. CLIP identifies Nova-regulated RNA networks in the brain. Science. 2003;302:1212-5 pubmed..Thus, CLIP reveals that Nova coordinately regulates a biologically coherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that may relate to the cause of abnormal motor inhibition in POMA. ..
- Sabapathy K, Jochum W, Hochedlinger K, Chang L, Karin M, Wagner E. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev. 1999;89:115-24 pubmed..These results assign both pro- and anti-apoptotic functions for JNK1 and JNK2 in the development of the fetal brain. ..
- She Q, Chen N, Bode A, Flavell R, Dong Z. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 2002;62:1343-8 pubmed..These results suggest that JNK1 is a crucial suppressor of skin tumor development. ..
- Han Z, Boyle D, Chang L, Bennett B, Karin M, Yang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108:73-81 pubmed..Therefore, JNK is a critical MAPK pathway for IL-1--induced collagenase gene expression in synoviocytes and in joint arthritis, indicating that JNK is an important therapeutic target for RA. ..
- Tao J, Gao Y, Li M, He W, Chen L, Harvev B, et al. JNK2 negatively regulates CD8+ T cell effector function and anti-tumor immune response. Eur J Immunol. 2007;37:818-29 pubmed..In summary, our results demonstrate that JNK2 negatively regulates antigen-specific CD8+ T cell expansion and effector function, and thus selectively blocking JNK2 in CD8+ T cells may potentially enhance anti-tumor immune response. ..
- 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. ..
- Aurisicchio L, Di Lauro R, Zannini M. Identification of the thyroid transcription factor-1 as a target for rat MST2 kinase. J Biol Chem. 1998;273:1477-82 pubmed..Thus, TTF-1 represents the first identified target of this class of protein kinases. ..
- Santibanez J. JNK mediates TGF-beta1-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes. FEBS Lett. 2006;580:5385-91 pubmed..These results allow us to suggest a role of JNK in the TGF-beta1 induction of EMT in relation with the stimulation of malignant properties of mouse transformed keratinocytes. ..
- 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. ..
- Sluss H, Barrett T, Derijard B, Davis R. Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol. 1994;14:8376-84 pubmed..Together, these data indicate a role for the JNK group of protein kinases in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation. ..
- 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. ..
- Chen J, Lu D, Chia C, Ruan D, Sabapathy K, Xiao Z. Impaired long-term potentiation in c-Jun N-terminal kinase 2-deficient mice. J Neurochem. 2005;93:463-73 pubmed..Together, the data highlight the specific role of JNK2 in hippocampal synaptic plasticity during development. ..
- Lee Y, Cho H, Jeoung D, Soh J, Cho C, Bae S, et al. HSP25 overexpression attenuates oxidative stress-induced apoptosis: roles of ERK1/2 signaling and manganese superoxide dismutase. Free Radic Biol Med. 2004;36:429-44 pubmed..From the above results, we suggest for the first time that reduced oxidative damage by HSP25 was due to MnSOD-mediated downregulation of ERK1/2. ..
- Zhu X, Raina A, Rottkamp C, Aliev G, Perry G, Boux H, et al. Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J Neurochem. 2001;76:435-41 pubmed..Together, these findings suggest that JNK/SAPK dysregulation, probably resulting from oxidative stress, plays an important role in the increased phosphorylation of cytoskeletal proteins found in AD. ..
- Abulencia J, Gaspard R, Healy Z, Gaarde W, Quackenbush J, Konstantopoulos K. Shear-induced cyclooxygenase-2 via a JNK2/c-Jun-dependent pathway regulates prostaglandin receptor expression in chondrocytic cells. J Biol Chem. 2003;278:28388-94 pubmed..Hence, a biochemical pathway exists wherein fluid shear activates COX-2, via a JNK2/c-Jun-dependent pathway, which in turn elicits downstream EP2 and EP3a1 mRNA synthesis. ..
- 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. ..
- 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. ..
- Kim H, Jung K, Yu B, Cho C, Chung H. Influence of aging and calorie restriction on MAPKs activity in rat kidney. Exp Gerontol. 2002;37:1041-53 pubmed..Based on these data, we concluded that an age-related increase in MAPK activity is associated with increased ROS, which was effectively suppressed by the anti-oxidative action of CR. ..
- 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. ..
- Duyndam M, Hulscher S, van der Wall E, Pinedo H, Boven E. Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent induction of vascular endothelial growth factor expression by sodium arsenite. J Biol Chem. 2003;278:6885-95 pubmed..Altogether, these data suggest that not HIF-1, but rather p38, mediates induction of VEGF mRNA expression by sodium arsenite. ..
- Angell R, Atkinson F, Brown M, Chuang T, Christopher J, Cichy Knight M, et al. N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3. Bioorg Med Chem Lett. 2007;17:1296-301 pubmed..X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site. ..
- 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. ..
- Dong C, Davis R, Flavell R. Signaling by the JNK group of MAP kinases. c-jun N-terminal Kinase. J Clin Immunol. 2001;21:253-7 pubmed..In this review, we summarize these advances in understanding the expression, function, and regulation of the JNK pathway in T-lymphocyte activation and differentiation. ..
- Wang L, Zhang Y, Li H, Xu Z, Santella R, Weinstein I. Hint1 inhibits growth and activator protein-1 activity in human colon cancer cells. Cancer Res. 2007;67:4700-8 pubmed..These results suggest that HINT1 inhibits AP-1 activity by binding to a POSH-JNK2 complex, thus inhibiting the phosphorylation of c-Jun. This effect could contribute to the tumor suppressor activity of HINT1. ..
- Kolfschoten G, Hulscher T, Duyndam M, Pinedo H, Boven E. Variation in the kinetics of caspase-3 activation, Bcl-2 phosphorylation and apoptotic morphology in unselected human ovarian cancer cell lines as a response to docetaxel. Biochem Pharmacol. 2002;63:733-43 pubmed..We conclude that docetaxel is able to activate caspase-3, induce Bcl-2 phosphorylation and apoptosis in cells that show a prolonged G2/M arrest, but cells may also die by a caspase-3-independent cell death mechanism. ..
- Mynott T, Crossett B, Prathalingam S. Proteolytic inhibition of Salmonella enterica serovar typhimurium-induced activation of the mitogen-activated protein kinases ERK and JNK in cultured human intestinal cells. Infect Immun. 2002;70:86-95 pubmed..Data also confirm that bromelain is a novel inhibitor of MAP kinase signaling pathways and suggest a novel role for proteases as inhibitors of signal transduction pathways in intestinal epithelial cells. ..
- Nicolson K, Freland S, Weir C, Delahunt B, Flavell R, Bäckström B. Induction of experimental autoimmune encephalomyelitis in the absence of c-Jun N-terminal kinase 2. Int Immunol. 2002;14:849-56 pubmed
- Jeon E, Song H, Kim M, Moon H, Bae Y, Jung J, et al. Sphingosylphosphorylcholine induces proliferation of human adipose tissue-derived mesenchymal stem cells via activation of JNK. J Lipid Res. 2006;47:653-64 pubmed..These results indicate that SPC stimulates the proliferation of hADSCs through the Gi/Go-PLC-JNK pathway and that LPA receptors may be responsible in part for the SPC-induced proliferation. ..
- 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. ..
- Sabapathy K, Wagner E. JNK2: a negative regulator of cellular proliferation. Cell Cycle. 2004;3:1520-3 pubmed..These data therefore suggests that JNK2, in contrast to JNK1, is a negative regulator of cellular proliferation in multiple cell types. ..
- Vanlandschoot P, Roobrouck A, Van Houtte F, Leroux Roels G. Recombinant HBsAg, an apoptotic-like lipoprotein, interferes with the LPS-induced activation of ERK-1/2 and JNK-1/2 in monocytes. Biochem Biophys Res Commun. 2002;297:486-91 pubmed..Addition of rHBsAg to LPS-stimulated cells reduces TNFalpha mRNA levels, but does not affect phosphorylation of p65 NF-kappaB and p38 MAP kinase. Instead, a reduced phosphorylation of ERK-1/2 and JNK-1/2 MAP kinases is observed. ..
- Fan M, Goodwin M, Vu T, Brantley Finley C, Gaarde W, Chambers T. Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. J Biol Chem. 2000;275:29980-5 pubmed..These results provide evidence for a direct role of the JNK pathway in apoptotic regulation through Bcl-2/Bcl-X(L) phosphorylation. ..