Nectin-4 (gene name PVRL4, poliovirus receptor-like 4) is a 66 kDa type I transmembrane glycoprotein belonging to the Nectin family of Ig superfamily proteins (1). The Latin word necto means “to connect”, indicating the role of nectins in Ca2+‑independent cell-cell adhesion (2). Nectin-4 forms homodimers in cis, followed by interactions in trans with Nectin-1 or -4 (1 ‑ 3). Mouse Nectin-4 mRNA is found in the embryo, lung, testis and brain, while in the human it is normally expressed in the placenta, especially in endothelial cells (1, 4, 5). Mouse Nectin-4 cDNA encodes 508 amino acids (aa), including a 30 aa signal sequence, a 317 aa extracellular domain (ECD), a 21 aa transmembrane segment (TM), and a 140 aa cytoplasmic region. Nectin ECDs contain three Ig-like domains: an N‑terminal V-type that mediates ligand binding, and two C2-type (3). One isoform lacks aa 410-434 in the cytoplasmic domain (1). In many human ductal breast or non-small cell lung carcinomas, Nectin-4 is up-regulated and a soluble 43 kDa form is found in the plasma (4 ‑ 6). This form is generated from the membrane protein via the action of TACE/ADAM-17 (6). The extracellular domain of mouse Nectin-4 shares 91%, 97%, 92%, 90% and 89% amino acid sequence homology with the corresponding regions of human, rat, canine, porcine and bovine Nectin-4, respectively. In forming adherens junctions, trans interactions of Nectin-4 initiate cell-cell interactions and recruit intracellular cadherins through afadin and other junctional proteins (1, 2). These interactions organize the actin cytoskeleton, strengthen attachment to basement membrane and promote further cell-cell connections (2, 7).
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