C-Jun-amino-terminal kinase-interacting protein 1; JIP-1; JNK-interacting protein 1; islet-brain 1; IB-1; JNK MAP kinase scaffold protein 1; mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1, IB1, JIP,1 PRKM8IP)
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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 & inhibiting JNK phosphorylation of c-Jun
- may also participate in apoER2-specific reelin signaling
- directly, or indirectly, regulates GLUT2 gene expression & beta-cell function
- appears to have a role in cell signaling in mature & developing nerve terminals
- may function as a regulator of vesicle transport, through interactions with the JNK-signaling components & motor proteins (putative)
- functions as an anti-apoptotic protein & whose level seems to influence the beta-cell death or survival response
- phosphorylated by MAPK8, MAPK9 & MAPK10
- phosphorylation on Thr-103 is also necessary for the dissociation & activation of MAP3K12
- ubiquitinated
- two preliminary events are required to prime for ubiquitination
- phosphorylation
- an increased in intracellular Ca+2 concentration
- then, the Ca+2 influx initiates ubiquitination & degradation by the ubiquitin-proteasome pathway
- forms homo- or heterooligomeric complexes
- binds specific components of the JNK signaling pathway namely, MAPK8, MAPK9, MAPK10, MAPKK7, MLK2, MLK3, MAP3K12 & MAP3K13
- also binds the proline-rich domain-containing splice variant of apolipoprotein E receptor 2 (apoER2)
- interacts, via the PID domain, with RGNEF
- binds the cytoplasmic tails of LRP1 & LRP2 (megalin)
- binds the TPR motif-containing C-terminal of KNS2, then the pre-assembled MAPK8IP1 scaffolding complexes are transported as a cargo of kinesin, to the required subcellular location
- interacts with the cytoplasmic domain of APP (putative)
- DNA-binding transactivator of the glucose transporter GLUT2
Structure
- 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, & prevents activation of c-jun by MAPK8, MAPK9 & MAPK10
- belongs to the JIP scaffold family
- contains 1 PID domain
- contains 1 SH3 domain
Compartment
- cytoplasm (putative), perinuclear region (putative), nucleus
- 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 & nucleus (putative)
Expression
- highly expressed in brain
- expressed in neurons, localizing to neurite tips in differentiating cell
- also expressed in the pancreas, testis & prostate
- low levels in heart, ovary & small intestine
- decreased levels in pancreatic beta cells sensitize cells to IL-1-beta-induced apoptosis
Pathology
- defects in MAPK8IP1 are a cause of diabetes mellitus type 2
Notes
- a chemically synthesized cell-permeable peptide of the minimal inhibitory domain decreases brain lesions in both transient & permanent ischemia
- the level of protection is still high when administered 6-12 hours after ischemia
More general terms
Additional terms
References
- ↑ Waeber G et al The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nature Genetics 24:291-5, 2000 PMID: https://www.ncbi.nlm.nih.gov/pubmed/10700186
- ↑ UniProt http://www.uniprot.org/uniprot/Q9UQF2.html