Function: The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
Tissue specificity: Highly expressed in brain. Expressed in neurons, localizing to neurite tips in differentiating cells. Also expressed in the pancreas, testis and prostate. Low levels in heart, ovary and small intestine. Decreased levels in pancreatic beta cells sensitize cells to IL-1-beta-induced apoptosis.
Disease: Diabetes mellitus, non-insulin-dependent
Similarity: Belongs to the JIP scaffold family.
Contains 1 PID domain.
Contains 1 SH3 domain.
Domain: The destruction boxes (D-box) may act as recognition signals for degradation via the ubiquitin-proteasome pathway.
A minimal inhibitory domain prevents pancreatic beta cell apoptosis in vitro, and prevents activation of c-jun by MAPK8, MAPK9 and MAPK10.
The SH3 domain mediates homodimerization.
PTM: Phosphorylated by MAPK8, MAPK9 and MAPK10. Phosphorylation on Thr-103 is also necessary for the dissociation and activation of MAP3K12. Phosphorylated by isoform 1 and isoform 2 of VRK2. Hyperphosphorylated during mitosis following activation of stress-activated and MAP kinases.
Ubiquitinated. Two preliminary events are required to prime for ubiquitination; phosphorylation and an increased in intracellular calcium concentration. Then, the calcium influx initiates ubiquitination and degradation by the ubiquitin-proteasome pathway.
Cytoplasmic. Accumulates in cell surface projections. Under certain stress conditions, translocates to the perinuclear region of neurons. In insulin-secreting cells, detected in both the cytoplasm and nucleus