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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)

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 a) phosphorylation b) 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

Related

diabetes mellitus type 2 (insulin-resistant)

General

c-jun-amino-terminal kinase interacting protein (JNK-interacting protein, JIP, JNK MAP kinase scaffold protein) phosphoprotein

Properties

SIZE: entity length = 711 aa MW = 78 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: acidic region {42-48} MOTIF: acidic residue (SEVERAL) glycine-rich region {79-84} Thr phosphorylation site {T103} acidic region {107-116} MOTIF: acidic residue (SEVERAL) binding site SITE: 127-285 FOR-BINDING-OF: c-jun NH2 terminal kinase, jun kinase (JNK) or stress-activated protein kinase (SAPK) MOTIF: domain {157-176} Thr phosphorylation site {T205} glutamate-rich region {331-334} MOTIF: glutamate residue (SEVERAL) ubiquitination site (destruction box, D-box) SITE: 353-360 FOR-BINDING-OF: ubiquitin proline-rich region SITE: 359-363 MOTIF: proline residue (SEVERAL) ubiquitination site (destruction box, D-box) SITE: 364-372 FOR-BINDING-OF: ubiquitin src homology 3 [SH3] domain SITE: 488-549 phosphotyrosine interaction domain NAME: phosphotyrosine interaction domain SITE: 561-700

Database Correlations

OMIM correlations MORBIDMAP 604641 UniProt Q9UQF2 PFAM correlations Entrez Gene 9479 Kegg hsa:9479

References

  1. 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: 10700186
  2. UniProt :accession Q9UQF2