CD27 Signaling in Lymphocytes


Pathway Description

CD27 is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily, which includes TNFR types I and II, Nerve Growth Factor Receptor (NGFR), CD30 (associated with Hodgkin lymphoma), Fas/Apo1 (CD95), CD40, 4-1BB, and OX40. Members of the TNFR superfamily are important for cell growth and survival. These receptors are known to play a very important role in cell growth and differentiation, as well as apoptosis or programmed cell death.In addition to providing costimulatory signals for cell proliferation, ligation of both TNFR1 and Fas can result in programmed cell death or apoptosis. The underlying mechanism requires an intact 80-aa stretch present in the cytoplasmic tails of both TNFR1 and Fas, termed the DD (Death Domain). CD27 is a disulfide-linked 120-kDa type I transmembrane glycoprotein belonging to the TNFR family and is expressed by the majority of peripheral T-Cells, medullary thymocytes, natural killer cells and B-Cells. CD70, a ligand for CD27 is a type II transmembrane glycoprotein belonging to the TNF family and is expressed by activated T-Cells and B-Cells.

Unlike TNFR1 and Fas, the cytoplasmic tail of CD27 is relatively short and lacks the DD but a novel protein Siva binds to the CD27 cytoplasmic tail. It has a DD homology region, a box-B-like ring finger, and a zinc finger-like domain. Overexpression of Siva in various cell lines induces apoptosis, suggesting an important role for Siva in the CD27-transduced apoptotic pathway. Siva interacts with the cytoplasmic tail of CD27, providing death domain-like structures. The further events of this apoptotic pathway are unknown so far. Due to the fact that CD27 belongs to the TNF receptor superfamily, it is quite possible that a protein which is similar to FADD-a protein which is necessary for the Fas/Fas ligand-caused apoptosis-binds to Siva and induces the activation of a putative Caspase. Therefore, this activation might be responsible for the activation of effector Caspases (e.g., Caspase3) and finally for the induction of programmed cell death.

CD27 associates with TRAF2 and TRAF5, and these TRAFs are implicated in NF-κB and SAPK/JNK activation by CD27. Recent reports indicated that TRAF2 activates NIK, and NIK, in turn, activates IKK1 and IKK2; these three kinases form a complex, resulting in the phosphorylation of I-κB and its degradation, which leads to NF-κB activation. At present, it is unlikely that the activation of TRAF-NF-κB activation cascade induces calcium mobilization, protein kinase C activation, or protein tyrosine kinase activation. Therefore, CD27 may also activate multiple signaling pathways as observed in tyrosine kinase receptors and cytokine receptors. CD27, a member of this family, is mainly expressed on discrete populations of T and B-Cells where it appears to provide crucial co-stimulatory signals for T-Cell activation, B- A role for CD27 has been implicated in various types of autoimmune disorders and certain B-Cell cancers.


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