Disease relevance of MAPK9

• Lastly, inhibition of JNK using both SP and antisense oligonucleotides targeted to JNK1 and JNK2 reduced proliferation of all three breast cancer cell lines [1].
• Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance [2].
• To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1(-/-) and Jnk2(-/-) mice and examined body weight and glucose metabolism in the resulting mutant allele combinations [2].
• Similarly, reduction of JNK1 in human hepatoma cells decreased TBP expression, whereas reduction of JNK2 enhanced it [3].
• This suggests that SAPKgamma/JNK1 and SAPKalpha/JNK2 may be important mediators of stress-induced responses in early implanting conceptuses that could mediate embryo loss [4].

High impact information on MAPK9

• JNK2 binds c-Jun approximately 25 times more efficiently than JNK1, and as a result has a lower Km toward c-Jun than JNK1 [5].
• JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation [5].
• Finally, we showed that CARMA1- and Bcl10-mediated JNK2 activation had a critical role in regulating the amount of c-Jun protein [6].
• The CARMA1-Bcl10 Signaling Complex Selectively Regulates JNK2 Kinase in the T Cell Receptor-Signaling Pathway [6].
• Analysis of other members of the MAP kinase family showed that chondrocytes also express c-Jun NH2 terminal kinase (JNK)-1, JNK-2, and p38 proteins [7].

Biological context of MAPK9

• Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner [8].
• Furthermore, UVB-induced H3 phosphorylation at serine 28 was inhibited in Jnk1(-/-) cells but not in Jnk2(-/-) cells [9].
• These studies uncovered several new molecular events that distinguish the functions of JNK1 and JNK2 that are critical for their regulation of cellular proliferation [3].
• SAPKgamma/JNK1 and SAPKalpha/JNK2 mRNA transcripts are expressed in early gestation human placenta and mouse eggs, preimplantation embryos, and trophoblast stem cells [4].
• This study represents the first demonstration of a cellular phenotype regulated by a JNK isoform family, JNK2 [10].

Anatomical context of MAPK9

• Treatment of K562 cells with PBOX-6 resulted in the transient activation of two JNK isoforms, JNK1 and JNK2 [11].
• Similarly, inhibition of JNK1 and JNK2 activities by the selective inhibitor SP600125 led to both dose-dependent reduction of c-jun and ATF-2 phosphorylation, and of the differentiation of HL60 cells [12].
• Relative to wild-type fibroblasts, TBP was decreased in Jnk1(-/-) cells and increased in Jnk2(-/-) cells [3].
• RESULT(S): SAPKgamma/JNK1 and SAPKalpha/JNK2 mRNA transcripts are present in early-gestation human placenta, a human trophoblast cell line, mouse eggs, preimplantation embryos, and a mouse trophoblast cell line at levels similar to positive control levels [4].
• Suppression of JNK2 phosphotransferase activity by NO is also supported by the observation that NO plays an important anti-apoptotic roles in heptocytes, splenocytes, eosinophils and B lymphocytes [13].

Associations of MAPK9 with chemical compounds

• JNK1 or JNK2 was able also to phosphorylate H3 at serine 28 in vitro but to a lesser degree [9].
• Reduced form of glutathione protects the GSNO-induced suppression of JNK2 activation in a dose-dependent fashion [13].
• Nitric oxide inhibits c-Jun N-terminal kinase 2 (JNK2) via S-nitrosylation [13].
• S-nitrosylation by S-nitrosoglutathione (GSNO), a nitric oxide (NO) donor, suppresses the phosphotransferase activity of cJun N-terminal kinase 2 (JNK2)/stress activated protein kinase (SAPK) in dose- and time-dependent manners in vitro [13].
• Although both JNK isoforms phosphorylate the NH2-terminal activation domain of the transcription factor c-Jun, the activity of JNK2 was approximately 10-fold greater than that of JNK1 [14].

Physical interactions of MAPK9

• Phosphorylated JNK2 binds to JIP1, and the phosphorylation of the Thr-183 residue of JNK2 occurs [15].

Enzymatic interactions of MAPK9

• The activated SEK1 dissociates from JIP3 and phosphorylates JNK2 on the Tyr-185 residue [15].
• MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro, Ser-407 being phosphorylated much more rapidly than Thr-183 in vitro [16].
• We showed that treatment of HeLa cells with MG132, a proteasome inhibitor and known INK activator, caused the transcriptional activation domain of HSF1 to be targeted and phosphorylated by JNK2 in vivo [17].
• Phosphopeptide mapping of MLK2 proteins revealed that activated JNK2 phosphorylates multiple sites mainly within the noncatalytic C-terminal region of MLK2 including the C-terminal 100 amino acid peptide [18].
• Upon stress, TIF-IA is phosphorylated by c-Jun N-terminal kinase 2 (JNK2) [19].

Regulatory relationships of MAPK9

• Knockdown of either JNK1 or JNK2 with small interfering RNA also significantly reduced the regulated PTX3 expression [20].
• Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX-induced MRP1 expression [21].

Other interactions of MAPK9

• These protein kinases correspond to alternatively spliced isoforms derived from the JNK1, JNK2 and JNK3 genes [22].
• To investigate the growth-regulatory functions of JNK1 and JNK2, we used specific antisense oligonucleotides (AS) to inhibit their expression [8].
• Taken together, these results indicate that JNK is required for growth of T98G cells in nonstress conditions and that p21(cip1/waf1) may contribute to the sustained growth arrest of JNK2-depleted T98G cultures [23].
• An acute increase in IVC intraluminal pressure failed to increase the phosphorylation of ERK1-, JNK-2, or any of the p38-MAPKs in the diabetic obese Zucker rats [24].
• Shear-induced cyclooxygenase-2 via a JNK2/c-Jun-dependent pathway regulates prostaglandin receptor expression in chondrocytic cells [25].

Analytical, diagnostic and therapeutic context of MAPK9

• Analysis with an Affymetrix cDNA array suggested that SAPKalpha/JNK2 and 38 kDa mitogen-activated protein kinase had the highest mRNA expression measured for each of three family members [4].
• DESIGN: Whole RNA was isolated from the tissue sources listed above and control tissues, and reverse transcription-polymerase chain reaction (RT-PCR) was performed to assay for the qualitative and semiquantitative presence of SAPKgamma/JNK1, SAPKalpha/JNK2, and SAPKbeta/JNK3 [4].
• Here, we report the molecular cloning of the 55-kD form of JNK, JNK2, which exhibits 83% identity and similar regulation to JNK1 [5].
• Moreover, systemic treatment of mice bearing established xenografts of PC3 prostate carcinoma cells with antisense JNK1 and JNK2 led to inhibition tumor growth by 57% (P < 0.002) and 80% (P < 0.001), respectively [26].
• Thus, JNKs the relevant MAP kinases for the NGF-induced formation and elongation of PC12 cells, and this process is also supported by JNK2 and JNK3 which are commonly considered as pro-apoptotic signal transducers [27].

References