General annotation |
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. |
Cofactor |
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Subunit structure |
Forms homo- or heterooligomeric complexes. Binds specific components of the JNK signaling pathway namely, MAPK8, MAPK9, MAPK10, MAPKK7, MLK2, MLK3, MAP3K12 and 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 and 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 (By similarity). |
Subcellular location |
Cytoplasm (By similarity). Cytoplasm, perinuclear region (By similarity). Nucleus (By similarity). Note=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 (By similarity). |
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. |
Induction |
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Domain |
A minimal inhibitory domain prevents pancreatic beta cell apoptosis in vitro, and prevents activation of c-jun by MAPK8, MAPK9 and MAPK10. |
Post-translational modification |
Phosphorylated by MAPK8, MAPK9 and MAPK10. Phosphorylation onThr-103 is also necessary for the dissociation and activation ofMAP3K12. Ubiquitinated. Two preliminary events are required to primefor ubiquitination; phosphorylation and an increased inintracellular calcium concentration. Then, the calcium influxinitiates ubiquitination and degradation by the ubiquitin-proteasome pathway. |
Involvement in disease |
Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance. |
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References |
"Genomic organization, fine-mapping, and expression of the humanislet-brain 1 (IB1)/C-jun-amino-terminal kinase interacting protein-1(JIP-1) gene.";,Mooser V., Maillard A., Bonny C., Steinmann M., Shaw P., Yarnall D.P.,Burns D.K., Schorderet D.F., Nicod P., Waeber G.;,Genomics 55:202-208(1999)., PubMeb:9933567 DOI:10.1006/geno.1998.5641
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,Venter J.C.;,Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
Yu W., Sarginson J., Gibbs R.A.;,Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases.
"Interaction of c-Jun amino-terminal kinase interacting protein-1 withp190 rhoGEF and its localization in differentiated neurons.";,Meyer D., Liu A., Margolis B.;,J. Biol. Chem. 274:35113-35118(1999)., PubMeb:10574993 DOI:10.1074/jbc.274.49.35113
"Cargo of kinesin identified as JIP scaffolding proteins andassociated signaling molecules.";,Verhey K.J., Meyer D., Deehan R., Blenis J., Schnapp B.J.,Rapoport T.A., Margolis B.;,J. Cell Biol. 152:959-970(2001)., PubMeb:11238452 DOI:10.1083/jcb.152.5.959
"Mixed lineage kinase LZK forms a functional signaling complex withJIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinasepathway.";,Ikeda A., Hasegawa K., Masaki M., Moriguchi T., Nishida E.,Kozutsumi Y., Oka S., Kawasaki T.;,J. Biochem. 130:773-781(2001)., PubMeb:11726277
"Interaction of Alzheimer's beta-amyloid precursor family proteinswith scaffold proteins of the JNK signaling cascade.";,Taru H., Iijima K., Hase M., Kirino Y., Yagi Y., Suzuki T.;,J. Biol. Chem. 277:20070-20078(2002)., PubMeb:11912189 DOI:10.1074/jbc.M108372200
"Recruitment of JNK to JIP1 and JNK-dependent JIP1 phosphorylationregulates JNK module dynamics and activation.";,Nihalani D., Wong H.N., Holzman L.B.;,J. Biol. Chem. 278:28694-28702(2003).,PubMeb:12756254 DOI:10.1074/jbc.M304212200
"Cell-permeable peptide inhibitors of JNK: novel blockers of beta-celldeath.";,Bonny C., Oberson A., Negri S., Sauser C., Schorderet D.F.;,Diabetes 50:77-82(2001).,PubMeb:11147798
"Calcium- and proteasome-dependent degradation of the JNK scaffoldprotein islet-brain 1.";,Allaman-Pillet N., Storling J., Oberson A., Roduit R., Negri S.,Sauser C., Nicod P., Beckmann J.S., Schorderet D.F.,Mandrup-Poulsen T., Bonny C.;,J. Biol. Chem. 278:48720-48726(2003).,PubMeb:14507925 DOI:10.1074/jbc.M306745200
"A peptide inhibitor of c-Jun N-terminal kinase protects againstexcitotoxicity and cerebral ischemia.";,Borsello T., Clarke P.G., Hirt L., Vercelli A., Repici M.,Schorderet D.F., Bogousslavsky J., Bonny C.;,Nat. Med. 9:1180-1186(2003).,PubMeb:12937412 DOI:10.1038/nm911
"The gene, MAPK8IP1, encoding islet-brain-1, is a candidate for type 2diabetes.";,Waeber G., Delplanque J., Bonny C., Mooser V., Steinmann M.,Widmann C., Maillard A., Miklossy J., Dina C., Hani E.H., Vionnet N.,Nicod P., Boutin P., Froguel P.;,Nat. Genet. 24:291-295(2000)., PubMeb:10700186 DOI:10.1038/73523 |
