April Mediated Signaling

A proliferation-inducing ligand (APRIL), also known as TNF and ApoL related leukocyte expressed ligand 2 (TALL2), is a recently identified TNF ligand family member implicated in immune regulation. APRIL is a type II membrane protein with a predicted cytoplasmic domain, a hydrophobic transmembrane region and an extracellular domain of 201 amino acids. APRIL shows a unique maturation pathway among the TNF ligand family members as it is not detectable as a membrane anchored protein at the cell surface, but is processed in the golgi apparatus prior to its secretion. APRIL acts solely as a secreted factor.Two members of the TNF receptor family, the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), have been identified as receptors that can bind APRIL. APRIL promotes B-cell proliferation by binding to the BCMA and TACI receptors, which are expressed on resting and activated B-cells. In addition, TACI has been found on a subset of activated T cells.Engagement of BCMA activates JNK, p38 MAPK and the transcription factors NF-κB and Elk1 via TRAF1, 2 and 3, whereas cross-linking of TACI activates the transcription factors NF-κB and NFAT. TACI intracellular domain interacts with TRAF 2, 5, and 6 and transduces signals necessary for B-Cell proliferation and survival. TRAFs recruit IKK-activating kinases such as NIK, MEKK1 and TAK1 to phosphorylate IKK, which leads to NF-κB activation. A family of inhibitory proteins, IκBs, binds to NF-κB and controls the activity of NF-κB. Exposure of cells to extracellular stimuli that perturb redox balance results in rapid phosphorylation, ubiquitination, and proteolytic degradation of IκBs. This process frees NF-κB from the NF-κB/IκB complex and enables NF-κB to translocate to the nucleus where it regulates gene transcription.APRIL is predominantly expressed in malignant tumors and promotes growth in several malignant tumor cell lines in vitro and in vivo.