A proliferation-inducing ligand (APRIL, also known as TNFSF13) belongs to the tumor necrosis factor (TNF) ligand superfamily member 13. APRIL is expressed as a type-II transmembrane protein, but unlike most other TNF family members, it is rarely expressed at the cell membrane. Instead, it is cleaved in the Golgi apparatus by a furin convertase to release a soluble active form, which is subsequently secreted. APRIL has a 28-amino-acid cytoplasmic domain, a transmembrane domain, and a 201-residue extracellular domain consisting of a stalk and a TNF domain. Soluble, mature APRIL is an approximately 63-kDa non-covalent trimer. APRIL can also be exposed on the cell surface due to unique intergenic splicing between the TNF-related weak inducer of apoptosis (TWEAK) and APRIL locus, giving rise to a fusion protein called TWEPRIL. APRIL is closely related to the B cell-activating factor (BAFF), a member of the TNF ligand family. APRIL is expressed by a variety of immune cell subsets that also produce BAFF: monocytes, macrophages, dendritic cells (DCs), neutrophils, and T cells.
APRIL binds to two known TNF receptors, CAML interactor (TACI) and B cell maturation antigen (BCMA). Specific signaling via BCMA has been shown to drive activation of p38 mitogen activating protein kinase (MAPK) and c-Jun NH2-terminal Kinase (JNK) pathways, again to stimulate either survival and/or proliferation. TACI was originally shown to be a CAML interacting receptor, which can signal via the NFAT/AP-1 pathway, but it was later shown that ligation of TACI can also signal activation of NF-kB and JNK. APRIL signaling via TACI was shown to be responsible for class switch recombination of IgG and IgA, as well as cell survival, PKA activation, and the down-regulation of several apoptotic regulators. Ligation of both BCMA and TACI leads to downstream activation of the classical NF-κB pathway that is thought to be at the crux of the proliferative signals delivered to malignant B-cells. In addition to binding to BCMA and TACI, APRIL interacts with heparan sulfate proteoglycans (HSPGs), which are structurally unrelated to TNF receptors. But currently, it is not clear whether these structures on membranes represent the unidentified third receptor.
Fig.1 APRIL exhibits diverse biological functions on normal and malignant cells. (Dillon, 2008)
High expression levels of APRIL mRNA were found in a panel of tumor cell lines as well as human primary tumors (Fig.1). Malignant B cells including those from chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphoma (NHL) patients, both respond to exogenous APRIL and express APRIL mRNA and protein. APRIL with high-level expression protects multiple myeloma cells from dexamethasone-induced cell death and activates the MAPK, AKT, and NF-κB signaling pathways. In addition, APRIL was discovered as a ligand over-expressed in solid tumors and it stimulates the proliferation of several malignant cell lines. In certain cases, it has been shown that APRIL found in histological samples is derived from the infiltrating cells, such as neutrophils and DCs, rather than the tumors themselves.
APRIL has roles in cell proliferation, differentiation, motility, trafficking, apoptosis, and tissue architecture. Creative Biolabs' expertise and our commitment to high-quality standards can provide one-stop customized tumor marker assay services. Our APRIL assay portfolio services for research include but are not limited to
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