cDNA cloning and mapping of a novel islet-brain/JNK-interacting protein

IB1/JIP-1 is a scaffold protein that regulates the c-Jun NH2-terminal kinas e (JNK) signaling pathway, which is activated by environmental stresses and /or by treatment with proinflammatory cytokines including IL-1 beta and TNF -alpha. The JNKs play an essential role in many biological processes, inclu ding the maturation and differentiation of immune cells and the apoptosis o f cell targets of the immune system. IB1 is expressed predominantly in brai n and pancreatic beta-cells where it protects cells from proapoptotic progr ams. Recently, a mutation in the amino-terminus of IB1 was associated with diabetes. A novel isoform, IB2, was cloned and characterized. Overall, both IBI and IB2 proteins share a very similar organization, with a JNK-binding domain, a Src homology 3 domain, a phosphotyrosine-interacting domain, and polyacidic and polyproline stretches located at similar positions. The IB2 gene (HGMW-approved symbol MAPK8IP2) maps to human chromosome 22q13 and co ntains 10 coding exons. Northern and RT-PCR analyses indicate that IB2 is e xpressed in brain and in pancreatic cells, including insulin-secreting cell s. IB2 interacts with both JNK and the JNK-kinase MKK7. In addition, ectopi c expression of the JNK-binding domain of IB2 decreases IL-1 beta-induced p ancreatic beta-cell death. These data establish IB2 as a novel scaffold pro tein that regulates the JNK signaling pathway in brain and pancreatic beta- cells and indicate that IB2 represents a novel candidate gene for diabetes. (C) 2000 Academic Press.