Disease relevance of MAPK8

• CONCLUSIONS: The inhibitory effect on JNK-c-Jun/AP-1 activation contributes to the antitumor effect of COX-2-specific inhibitor, and inhibition of JNK activation may have a therapeutic benefit against gastric cancer [1].
• Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade [2].
• These findings place DENN/MADD and JNK in important hypoxia insult-induced intracellular signaling pathways [3].
• Hepatitis B virus X protein (pX) activates p38 MAP kinase and JNK pathways and, in response to weak apoptotic signals, sensitizes hepatocytes to apoptosis [4].
• Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells [5].

Psychiatry related information on MAPK8

• Understanding the connection between AbetaPP phosphorylation and the JNK signaling pathway, which mediates cell response to stress may have important implications in understanding the pathogenesis of Alzheimer's disease [6].

High impact information on MAPK8

• In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity [7].
• Signal transduction by the JNK group of MAP kinases [8].
• The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis [9].
• Most importantly, JNK activation is not involved in induction of apoptosis, while activation of NF-kappaB protects against TNF-induced apoptosis [10].
• Recruitment of the signal transducer FADD to the TNFR1 complex mediates apoptosis but not NF-kappaB or JNK activation [10].

Chemical compound and disease context of MAPK8

• Using a tetracycline-regulated LMP-1 allele, we demonstrate that JNK is also an effector of non-cytotoxic LMP-1 signaling in B cells, the physiological target cells of EBV [2].
• Hepatoma cells treated with TNF and cycloheximide undergo apoptosis, which is proceeded by a strong activation of JNK [11].
• Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2 [12].
• These findings suggest that the preventing effect of quercetin on Ang II-induced VSMC hypertrophy are attributable, in part, to its inhibitory effect on Shc- and PI3-K-dependent JNK activation in VSMC [13].
• Extracellular signal-regulated protein kinase, but not c-Jun N-terminal kinase, is activated by type II gonadotropin-releasing hormone involved in the inhibition of ovarian cancer cell proliferation [14].

Biological context of MAPK8

• Therefore, SAPK activation occurs through a pathway that is not required for TNF-R1-induced apoptosis [15].
• The JNK protein kinase is a member of the MAP kinase group that is activated in response to dual phosphorylation on threonine and tyrosine [16].
• We have previously observed that metabolic oxidative stress-induced death domain-associated protein (Daxx) trafficking is mediated by the ASK1-SEK1-JNK1-HIPK1 signal transduction pathway [17].
• The dissociation of these two hormone actions shows that JNK nuclear transfer is dispensable for the downregulation of JNK activation by GCs [18].
• A proline-rich sequence of JNK1 is critical for the interaction of the kinase with the N-terminal Src homology 3 (SH3) domain of CrkII [19].

Anatomical context of MAPK8

• Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase [20].
• A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system [3].
• Employing hepatocyte cell lines expressing pX, which was regulated by tetracycline, we investigated the mechanism of apoptosis by p38 MAP kinase and JNK pathway activation [4].
• Taken together, our findings demonstrate the functional interaction of HPK1 with Crk and CrkL, reveal the downstream pathways of Crk- and CrkL-induced JNK activation, and highlight a potential role of HPK1 in T-cell activation [21].
• C-Jun amino-terminal kinase (JNK) was not tyrosine-phosphorylated by any cytokine despite the existence of JNK proteins in human neutrophils, whereas it was tyrosine-phosphorylated by TNF in undifferentiated and all-trans retinoic acid-differentiated HL-60 cells [22].

Associations of MAPK8 with chemical compounds

• In contrast, the SAPK1/JNK1 pathway was not regulated by any of these nonreceptor tyrosine kinases [23].
• Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity [24].
• When transcription was blocked by actinomycin D, JNK inhibition still enhanced apoptosis to a comparable extent [25].
• Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons [26].
• However, the molecular mechanism by which ceramide induces SAPK/JNK activation is unknown [27].
• We show that MLK2 and -3 are required for lipopolysaccharide, peptidoglycan, and FliC recruitment of JNK and p38 as well as for PAMP recruitment of the transcription factor c-Jun, and for the induction of interleukin-8 [28].
• A beta1 integrin-blocking antibody significantly inhibited JNK and paxillinTyr-118 phosphorylation and cell scattering, demonstrating that CagA-independent signaling required for cell motility occurs through beta1 [29].

Physical interactions of MAPK8

• A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates [30].
• We showed previously that MEKK1 binds directly to JNK/SAPK [31].
• However, the corresponding region of JNK bound by this JIP-1-based peptide was unknown [32].
• JNK inhibition with SP600125 also blocked binding of Sp1 to the DR5/TRAIL-R2 promoter [33].
• In addition, ectopic expression of the JNK-binding domain of IB2 decreases IL-1beta-induced pancreatic beta-cell death [34].

Enzymatic interactions of MAPK8

• We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity [35].
• Immunoblotting analysis indicated that JNK1 was phosphorylated by JNKK2 in the fusion protein on both Thr(183) and Tyr(185) residues [36].
• Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1 [6].
• ASK1 phosphorylates c-Jun N-terminal kinase (JNK) and elicits an apoptotic response [37].
• Furthermore, K8 was also phosphorylated on Ser-73 by JNK in vitro, yielding similar phosphopeptide maps as the in vivo phosphorylated material [38].

Co-localisations of MAPK8

• A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease [39].

Regulatory relationships of MAPK8

• Expression of HPK1 activates JNK1 specifically, and it elevates strongly AP-1-mediated transcriptional activity in vivo [40].
• Using this procedure, we identified the physiological substrates of several mitogen-activated protein kinase kinases and an authentic substrate of stress-activated protein kinase (SAPK) 2a/p38 [41].
• TNF-alpha-induced JNK activation was also inhibited in Ad5dnTRAF-2-infected HT-29 cells [42].
• Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways [43].
• Targeting of this partially active MLK3 to membranes likely results in additional phosphorylation events that fully activate MLK3 and its ability to maximally signal through the JNK pathway [44].
• Overall the results suggest that Vpr-(52-96)-activated JNK plays a key role in inducing apoptosis through the down-regulation of antiapoptotic Bcl2 and c-IAP1 genes [45].

Other interactions of MAPK8

• These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway [40].
• The protein kinase activity of these JNK isoforms was measured using the transcription factors ATF2, Elk-1 and members of the Jun family as substrates [16].
• Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids [18].
• Incubation of HUVEC with PD98059, which inhibits flow-mediated ERK1/2 activation, prevented flow from inhibiting cytokine activation of JNK [46].
• We also investigated the role of NIK in JNK activation by TNF [47].

Analytical, diagnostic and therapeutic context of MAPK8

• Ten JNK isoforms were identified in human brain by molecular cloning [16].
• In contrast, BCR ligation resulted in ERK-2 activation without significant SAPK activation [48].
• We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs [49].
• In addition, co-immunoprecipitation studies revealed that part of JNK is associated with K8 in vivo, correlating with decreased ability of JNK to phosphorylate the endogenous c-Jun [38].
• Immunofluorescence analysis revealed that the JNKK2-JNK1 fusion protein was predominantly located in the nucleus of transfected HeLa cells [36].

References