Thus associate with the CD40 signaling complex. While our previous work indicated a potentially important link between TRAF2 and HOIP in CD40 signaling, the signals and functions tested here are dependent upon TRAF6 as well as TRAF2. In previous experiments with TRAF-deficient A20.2J cells, we found that the activation of NF-kB by CD40 could be mediated by either TRAF2 or TRAF6, while activation of JNK by CD40 was largely dependent on TRAF6 alone. HOIP deficiency compromises the CD40-mediated activation of both NF-kB and JNK, indicating that signals mediated by both TRAF2 and TRAF6 likely pass through HOIP. Our previous work also demonstrated that the CD40-mediated activation of NF-kB and JNK, while TRAF6-dependent, was not compromised by the disruption of the binding site for TRAF6 in the cytoplasmic domain of CD40 or deletion of the receptor binding domain in TRAF6. These observations indicate that TRAF6 need not directly bind CD40 in order to mediate certain signals, suggesting the assembly of a signaling complex not directly associated with the receptor. If such a complex exists, our results indicate that the absence of HOIP compromises its function as well. Although the experiments presented here focus on CD40, our results and those of other groups support the possibility that HOIP is important in many signaling pathways in which TRAF2 or TRAF6 are involved, including those associated with various members of the TNF receptor superfamily and the Tolllike receptors. The potential importance of HOIP in immune function and TNFR family signaling is further supported by the recent discovery that HOIP interacts with a protein known as SHARPIN, which appears capable of working together with HOIP and HOIL to mediate the assembly of linear polyubiquitin. Tofacitinib 477600-75-2 Interestingly, mice with a spontaneous mutation in the gene encoding SHARPIN mice) exhibit chronic inflammation of the skin and internal organs, defective development of secondary lymphoid tissue, and defects in the production of switched immunoglobulin isotypes. The apparently intimate functional link between SHARPIN and HOIP strongly suggests that at least part of the cpdm phenotype stems from defects in the regulation or function of HOIP. The cerebellum forms as a result of a highly regulated programme of cell specification, proliferation, differentiation and migration. At the cellular level, the cerebellum is organised into distinct neuronal layers: the outermost molecular layer, the Purkinje cell monolayer, the densely populated internal granule layer and the innermost white matter.