NECTIN4 gene

The NECTIN4 gene (NECTIN4 stands for: Nectin Cell Adhesion Molecule 4) is a protein-coding gene located on chromosome 1q23.3. The NECTIN4 gene encodes a member of the nectin family. The encoded protein of the same name, a type I membrane protein, contains two immunoglobulin-like (Ig-like) C2 domains and one Ig-like V domain. The Nectin4 protein is involved in cell adhesion through transhomophilic and -heterophilic interactions. Alternatively spliced transcript variants have been found, but their full length and function have not yet been determined.

The type I membrane protein Nectin4 is characterized by a single membrane passage. A soluble form is produced by proteolytic cleavage at the cell surface by the metalloproteinase ADAM17/TACE. Signaling pathways associated with this protein include the organization of cell-cell junctions and the dynamics of Sertoli-Sertoli cell junctions . An important paralog of the NECTIN4 gene is NECTIN3 . The Nectin4 protein appears to be involved in cell adhesion via transhomophilic and -heterophilic interactions, the latter particularly involving interactions with Nectin1. In contrast to Nectin1, Nectin4 does not function as a receptor for the entry of alpha-herpesviruses into cells but as a receptor for measles virus.

Mutations in this gene cause ectodermal dysplasia-syndactyly syndrome type 1, an autosomal recessive disease.

It is of great clinical (and functional) importance that the secreted form of the protein is expressed by numerous tumor cell lines. For example, in breast tumors (especially in -triple-negative breast carcinoma), in urothelial carcinoma (urinary bladder, upper urinary tract - mostly expressed membranously, very high prevalence >80%; enfortumab vedotin is clinically established therapeutically - Klümper N et al. 2024), in non-small cell lung carcinoma (NSCLC / moderate to high expression), in pancreatic carcinoma (frequent overexpression, associated with aggressive behavior), in ovarian carcinoma (especially in serous high-grade carcinoma) and in esophageal and gastric carcinoma (variable, sometimes high expression, especially in adenocarcinomatous subtypes).

1. Eckstein M (2025). NECTIN4 amplification as a predictive biomarker for enfortumab vedotin response [NECTIN4 amplification as a predictive biomarker for enfortumab vedotin response]. Pathologie (Heidelb) Nov 14. doi: 10.1007/s00292-025-01496-w.
2. Klümper N et al. (2024) NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer. J Clin Oncol 42:2446-2455.
3. Wong RL et al. (2022) Enfortumab vedotin in the treatment of urothelial cancers and beyond. Future Oncol 18:3067-3084.