Disease relevance of MAPK10

• This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis [1].
• The c-Jun NH2-terminal kinase3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors [2].
• The p493F12 gene maps to the human chromosome 21q21 region, a region that may be important in the pathogenesis of AD and Down's syndrome [3].
• Akt inhibits MLK3/JNK3 signaling by inactivating Rac1: a protective mechanism against ischemic brain injury [4].
• These interactions are likely affected by a truncated JNK3 protein, and thereby provide an explanation for the link between alterations in MAP kinase signal transduction and brain disorders [5].

Psychiatry related information on MAPK10

• JNK3 is highly expressed and activated in postmortem brains of individuals that suffered from Alzheimer's disease [6].

High impact information on MAPK10

• One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system [7].
• These data indicate that the observed neuroprotection is due to the extinction of a Jnk3-mediated signalling pathway, which is an important component in the pathogenesis of glutamate neurotoxicity [7].
• Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene [7].
• Here we report that disruption of the gene encoding Jnk3 in mice caused the mice to be resistant to the excitotoxic glutamate-receptor agonist kainic acid: they showed a reduction in seizure activity and hippocampal neuron apoptosis was prevented [7].
• We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of beta-arrestin 2 using a yeast two-hybrid screen and by coimmunoprecipitation from mouse brain extracts or cotransfected COS-7 cells [8].

Chemical compound and disease context of MAPK10

• To further investigate the possible mechanism of JNK3 activation, antioxidant N-acetylcysteine (NAC) was given to the rats 20min prior to ischemia [9].

Biological context of MAPK10

• The mitogen-activated kinase activating death domain protein (MADD) that is differentially expressed in neoplastic vs. normal cells (DENN) was identified as a substrate for c-Jun N-terminal kinase 3, the first demonstration of such an activity for this stress-activated kinase that is predominantly expressed in the brain [10].
• Conservative mutations of the Asn-152 and Gln-155 residues inactivated the JNK3 enzyme, possibly interfering with protein folding in a critical hinge region of the protein [11].
• JNK3 alpha 1 is predominantly a neuronal specific MAP kinase that is believed to require, like all MAP kinases, both threonine and tyrosine phosphorylation for maximal enzyme activity [12].
• Reverse transcription and PCR revealed that JNK3 is endogenously expressed in SCLC cells, but not in either chromaffin or neuronally differentiated PC12 cells [13].
• In addition, experiments with Jnk(-/-) knockout mice have provided evidence that Jnk3 may be required for apoptosis in the hippocampus in vivo following injection of kainic acid, an excitotoxin, and that Jnk1 and Jnk2 are required for apoptosis in the developing embryonic neural tube [14].

Anatomical context of MAPK10

• The immunoprecipitation experiments showed that JNK3 isoform was predominantly activated upon hOLs exposure to TRAIL and JNK-3 activation occurred before mitochondrial membrane dysfunction [15].
• Keratinocytes express JNK-1 and JNK-3, which is unexpected because JNK-3 expression is considered brain-specific [16].
• Moreover for the first time, MAPK10/JNK3 was identified in human thyroid cells and tissue [17].
• Over-expression studies with the mutant protein in various cell lines, including neural cells, indicate that both its solubility and cellular localisation differ from that of the wild-type JNK3 [5].
• In addition, two known JNK3-interacting proteins, beta-arrestin 2 and JIP3, play established roles in neurite outgrowth and neurological development [5].

Associations of MAPK10 with chemical compounds

• Moreover, stimulation of the angiotensin II type 1A receptor activated JNK3 and triggered the colocalization of beta-arrestin 2 and active JNK3 to intracellular vesicles [8].
• Here we show that c-Jun N-terminal kinases JNK1, JNK2 and JNK3 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies [18].
• Our results suggest that activation of pro-apoptotic MLK3/JNK3 cascade can be suppressed through activating anti-apoptotic phosphoinositide 3-kinase/Akt pathway induced by a sublethal ischemic insult, which provides a functional link between Akt and the JNK family of stress-activated kinases in ischemic tolerance [19].
• Hypertonic stress, elicited by mannitol, also significantly stimulated these same JNKs, although the JNK3 isoforms were most strongly activated [13].
• Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3 [20].

Physical interactions of MAPK10

• Using the crystal structure of JNK3 complexed with JNK inhibitors, potential compound-interacting amino acid residues were mutated to the corresponding residues in p38 [11].
• It binds the upstream kinases ASK1 and MKK4 and couples stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic pool of JNK3 [21].

Regulatory relationships of MAPK10

• In contrast, MKK4-activated JNK3 alpha 1 had no increase in Vmax compared to nonactivated levels and had no phosphorylation on the basis of mass spectrometry [12].
• Beta-arrestin2 acts as a scaffold to enhance signaling to JNK3 stimulated by overexpression of the MAP3 kinase ASK1 or by agonist activation of the angiotensin 1A receptor [22].

Other interactions of MAPK10

• JNK2, which localized in the cytoplasm, or JNK3, which was confined in nucleus, remained in the same compartment after UV irradiation [23].
• The steady-state rate constants kcat, Km(GST-ATF2++), and Km(ATP) for both monophosphorylated and bisphosphorylated JNK3 alpha 1 were within 2-fold between the two enzyme forms, suggesting the addition of tyrosine phosphorylation does not affect the binding of ATF2, ATP, or maximal turnover [12].
• These data suggest that MKK7 was largely responsible for JNK3 alpha 1 activation and that a single threonine phosphorylation may be all that is needed for JNK3 alpha 1 to be active [12].
• Head-to-head juxtaposition of Fas-associated phosphatase-1 (FAP-1) and c-Jun NH2-terminal kinase 3 (JNK3) genes: genomic structure and seven polymorphisms of the FAP-1 gene [24].
• The data also indicate that the specific step enhanced by beta-arrestin2 involves phosphorylation of JNK3 by the MAP2 kinase MKK4 [22].

Analytical, diagnostic and therapeutic context of MAPK10

• Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt [19].
• 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 [25].
• A minor pool of phosphorylated JNK3 increased above the control level after reperfusion in hippocampal but not in neocortical particulate fractions [26].
• Here, examples are provided of how the combination of NMR SHAPES screening, virtual screening, molecular modeling and X-ray crystallography has led to novel drug scaffolds in several drug discovery programs: JNK3 MAP kinase and the fatty acid binding protein, aP2 [27].

References