Disease relevance of Mapk8ip

• Akt1 binding to JIP-1 acts as a regulatory gate preventing JNK activation, which is opened under conditions ischemia injury [1].
• These results point towards PIN and JIP-1 as antiapoptotic factors contributing to selective resistance of granule cells, whereas Caspase-3 may be involved in cell death of hippocampal CA1, CA3 and hilar neurons in the kainate epilepsy model [2].
• A neuroprotective protein, JNK-interacting protein 1 (JIP1), an inhibitor of JNK-mediated apoptosis, was reduced by 6-h hypoxia and markedly decreased by 24-h reoxygenation in CA1 neurons as was DENN/MADD, which also modulates JNK-mediated cell death [3].
• Here, we show that JNK activation is essential for alpha(1)AR-induced hypertrophy, in that alpha(1)AR-induced hypertrophic responses, such as reorganization of the actin cytoskeleton and increased protein synthesis, could be blocked by expressing the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of JNK [4].

High impact information on Mapk8ip

• Overexpression of Akt1 mutants that bind JIP1 reduced excitotoxic apoptosis [5].
• IB1 is expressed at high levels in neurons and in pancreatic beta-cells, where it controls expression of several insulin-secretory components and secretion [6].
• Taken together, these results indicate that IB1 homodimerization through its SH3 domain has pleiotropic effects including regulation of the insulin secretion process [6].
• IB1 has been shown to homodimerize, but neither the molecular mechanisms nor the function of dimerization have yet been characterized [6].
• The highly stable IB1 homodimer can be significantly destabilized in vitro by three individual point mutations directed against key residues involved in dimerization [6].

Chemical compound and disease context of Mapk8ip

• Administration of antioxidant N-acetylcysteine (NAC) can obviously affected the level of MLK3, JNK3 and Akt1 binding to JIP-1 and JNK3 activation in the hippocampus at 15min ischemia [1].

Biological context of Mapk8ip

• We then examined the potential role of IB1/JIP-1 in controlling TSH-beta gene expression [7].
• JIP-1 is a cytoplasmic inhibitor of the c-Jun amino-terminal kinase activated pathway recently cloned from a mouse brain cDNA library [8].
• We have therefore examined whether the JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1, a scaffold protein and specific inhibitor of JNK) can inhibit c-Jun phosphorylation and support the survival of sympathetic neurons deprived of NGF [9].
• Northern blot analysis confirmed upregulation of JIP-1 [10].
• However, activation of these reporter genes by PMA, which does not activate JNK significantly in myocytes, was much less affected by overexpression of JIP-1 [11].

Anatomical context of Mapk8ip

• Islet-brain-1 (IB1)/c-Jun N-terminal kinase interacting protein 1 (JIP-1) is a scaffold protein that is expressed at high levels in neurons and the endocrine pancreas [7].
• Herein, we examined expression of the gene encoding IB1/JIP-1 and its translated product in the anterior pituitary gland and a pituitary cell line, GH3 [7].
• IB1, a JIP-1-related nuclear protein present in insulin-secreting cells [8].
• We first detected the interaction of Akt1 and JIP-1 in hippocampus at various time points of ischemia [1].
• At the cellular level, JIP-1 was predominantly localized in cytoplasm, especially in the perinuclear area in retinal endothelial cells [10].

Associations of Mapk8ip with chemical compounds

• Thyrotropin-releasing hormone-stimulated thyrotropin expression involves islet-brain-1/c-Jun N-terminal kinase interacting protein-1 [7].
• In this study, we report the molecular cloning of novel isoforms of JIP-1, which harbor a putative phosphotyrosine interaction domain and a helix-loop-helix domain, as well as an SH3 homologous region in the C terminus [12].
• The result showed that the levels of MKK7 activation, translocation and binding of p-MKK7 to JIP-1 were obviously limited by N-acetylcysteine in the cytosol at 30 min after reperfusion [13].
• Overexpression of JIP-1 also significantly reduced the increase in cell area in response to PE from 63% to 56%, but had no effect on the increase in cell size in response to ET-1 (38%) [11].

Physical interactions of Mapk8ip

• IB1/JIP-1 interacts with the c-Jun N-terminal kinase and mediates the specific physiological stimuli (such as cytokines) [7].

Other interactions of Mapk8ip

• Together, these facts point to a central role of the IB1/JIP-1 protein in the control of TRH-mediated TSH-beta stimulation [7].

Analytical, diagnostic and therapeutic context of Mapk8ip

• X-ray crystallography studies show that the dimer interface covers a region usually engaged in PxxP-mediated ligand recognition, even though the IB1 SH3 domain lacks this motif [6].
• Molecular cloning of multiple splicing variants of JIP-1 preferentially expressed in brain [12].
• Immunoprecipitation showed that phosphorylated JNK, but not total JNK, coimmunoprecipitated with JIP-1 protein [10].
• The upregulation of growth arrest DNA damage induced gene (GADD153), brain-specific RING finger protein, JNK interacting protein (JIP-1), protein kinase A (PKA), and Na+K+ ATPase was studied by quantitative polymerase chain reaction (PCR) [14].

References