The NECTIN Family

1. Composition and Structural Characteristics of the NECTIN Family

1.1 Classification of NECTIN Family Members

The NECTIN family typically includes two related subgroups: Nectin and Nectin-like (Necl), comprising a total of nine members. The Nectin subgroup includes Nectin-1, Nectin-2, Nectin-3, and Nectin-4; the Necl subgroup includes Necl-1, Necl-2, Necl-3, Necl-4, and Necl-5. Each member has multiple names used across different research fields. The table below summarizes the commonly used aliases (including protein names, former gene symbols, and other database accession numbers) of each member to facilitate literature retrieval.

From an evolutionary and structural perspective, Nectin and Necl belong to the same related molecular family; however, the two subgroups exhibit significant differences in intracellular structure and signal connection modes, which constitute an important basis for their further functional diversification.

1.2 Common Structural Foundation

All NECTIN family members are single-pass transmembrane proteins whose basic structure consists of an extracellular region, a transmembrane region, and an intracellular region.

Most members possess a typical immunoglobulin-like structure in the extracellular region, usually comprising one IgV domain and two IgC2 domains. This region is responsible for mediating intercellular binding and serves as the primary basis for homophilic and heterophilic interactions within the NECTIN family.

Unlike cadherins, which depend on calcium ions to maintain cell-cell junctions, binding between NECTIN molecules relies primarily on spatial complementarity among immunoglobulin-like domains. Consequently, the NECTIN family can form more flexible recognition patterns between different cell types ^[1,2].

The intracellular region determines how different members participate in cellular signal regulation. The cytoplasmic tails of classical Nectin members can bind the adaptor protein Afadin, which in turn connects to the actin cytoskeleton, converting adhesion events at the cell surface into cytoskeletal rearrangements and signal responses ^[2].

In contrast, Necl members generally do not function through the classical Afadin pathway; instead, they participate in cell junctions, migration, and signal regulation through other intracellular binding proteins. This structural difference enables NECTIN family members, despite sharing similar extracellular structures, to engage in distinct biological processes.

3. Functions of NECTIN Family Members and Disease Research

Although NECTIN family members share similar structural foundations, they exhibit significant differences in tissue expression, binding partners, and biological functions. Among them, Nectin-1, Nectin-2/CD112, Nectin-4, and Necl-5/CD155 are the most intensively studied members, whereas CADM family members are primarily investigated in the context of the nervous system and tumors.

3.1 Nectin-1: A Cell Junction Molecule in Development and a Viral Entry Receptor

Nectin-1 (CD111) is one of the earliest discovered and most thoroughly studied Nectin members, widely expressed in epithelial tissues, the nervous system, and embryo development-related tissues. Its primary function is to participate in tissue architecture formation by mediating intercellular recognition and junctions.

During development, Nectin-1 is involved in cellular arrangement and morphogenesis across multiple tissues. Human genetic studies have found that mutations in the NECTIN1 gene can cause cleft lip/palate-ectodermal dysplasia syndrome (CLPED1), with patients exhibiting phenotypes such as cleft lip/palate, dental anomalies, and ectodermal tissue developmental defects ^[5]. This finding demonstrates that NECTIN1-mediated cell junctions are not only structurally significant but also indispensable regulatory factors in normal tissue development.

In addition to its role in tissue development, Nectin-1 holds important virological significance. Alphaherpesviruses such as herpes simplex virus type 1/2 (HSV-1/2) and pseudorabies virus (PRV) can exploit Nectin-1 as an important receptor for host cell entry, achieving viral-cell membrane fusion through binding of viral envelope glycoproteins to the Nectin-1 extracellular domain ^[6]. This discovery has made Nectin-1 an important molecule for studying viral infection mechanisms and host cell recognition.

Thus, Nectin-1 exemplifies a typical characteristic of the NECTIN family: the same cell surface adhesion molecule can participate in normal intercellular communication while also being exploited by pathogens to accomplish infection.

3.2 Nectin-2: A Critical Node Linking Cell Adhesion and Immune Regulation

Nectin-2 (CD112) is currently one of the most immunologically valuable members of the NECTIN family.

Early research primarily focused on the role of CD112 in cell junctions. Subsequent studies revealed that CD112 also serves as a ligand for multiple immune receptors, including CD226 (DNAM-1), TIGIT, and PVRIG, making it an important molecule linking cell surface recognition and immune regulation ^[7,8].

CD226 is an activating receptor predominantly expressed on natural killer (NK) cells and a subset of T cells. Binding of CD112 to CD226 can promote the recognition and killing of target cells by immune cells. However, CD112 can also bind the inhibitory receptor PVRIG and participate in the inhibition of T cell and NK cell function.

Therefore, CD112 does not possess a simple "activating" or "inhibitory" attribute; rather, it sits within a dynamic regulatory network. Competition among different receptors for CD112 binding can influence the direction of signals ultimately received by immune cells.

In the tumor microenvironment, tumor cells may influence immune cell recognition by altering CD112 expression levels. In recent years, research surrounding the CD112–PVRIG axis has gradually increased, and this pathway is considered a potential novel immune regulatory direction following PD-1/PD-L1 and TIGIT.

3.3 Nectin-3: Involvement in Neural Junctions and Germ Cell Interactions

Compared with Nectin-2 and Nectin-4, Nectin-3 has received less attention in disease research, yet its role in cell recognition within specific tissues is of significant importance.

The most prominent feature of Nectin-3 is its ability to form highly selective heterophilic binding with other Nectin members. For example, the interaction between Nectin-1 and Nectin-3 is believed to participate in cell recognition processes between nerve cells and within synaptic structures.

Cellular junctions in the nervous system are highly specific. Different types of nerve cells need to form stable connections at correct locations, and simple mechanical adhesion cannot meet such refined demands. Nectin-3 provides a molecular recognition mechanism for neural network formation through specific combinations with other members.

In addition, Nectin-3 participates in cell junctions within the reproductive system. Studies have shown that interactions among NECTIN family members are involved in maintaining junctions between Sertoli cells and germ cells during spermatogenesis ^[9].

At present, Nectin-3 has not yet become a clear drug development target, but it holds significant value for understanding tissue-specific cell recognition mechanisms.

3.4 Nectin-4: From a Development-Related Molecule to a Tumor Therapeutic Target

Nectin-4 (PVRL4) is currently the most clinically successful member of the NECTIN family.

Initially discovered in relation to embryonic tissue development, subsequent studies found that Nectin-4 is aberrantly expressed in a variety of tumor tissues, including urothelial carcinoma, breast cancer, lung cancer, and pancreatic cancer ^[10].

Compared with normal adult tissues, Nectin-4 expression is markedly elevated in some tumor cells. Additionally, its cell surface localization provides favorable antibody accessibility. These characteristics have made Nectin-4 an important candidate target for antibody drug development.

The most representative application to date is the Nectin-4-targeted antibody-drug conjugate (ADC), Enfortumab vedotin. This drug utilizes an anti-Nectin-4 antibody to recognize Nectin-4 on the tumor cell surface, and upon internalization, releases the cytotoxic payload MMAE, thereby exerting antitumor effects ^[11].

Clinical studies have demonstrated clear therapeutic efficacy of Enfortumab vedotin in patients with advanced urothelial carcinoma, and it has received regulatory approval for relevant indications ^[12]. Recently, the FDA further approved its combination with pembrolizumab for perioperative therapy in muscle-invasive bladder cancer (MIBC), regardless of cisplatin eligibility.

The successful validation of Nectin-4 is of great significance: it proves that cell adhesion molecules can serve not only as objects of disease mechanism research but also as direct drug development targets. Current research surrounding Nectin-4 has shifted from "whether it can be targeted" to how to optimize therapeutic outcomes, including expression heterogeneity, resistance mechanisms, and combination therapeutic strategies.

3.5 The CADM Family (Necl-1 to Necl-4): Research on Neural Functions and Tumors

The gene names for Necl-1 to Necl-4 are CADM3, CADM1, CADM2, and CADM4, respectively. It is worth noting that Necl-5 is not classified within the CADM family but is an independent member parallel to classical Nectin molecules. Compared with classical Nectin members, CADM family research is more concentrated in the nervous system and tumor-related fields.

Among them, CADM1 (Necl-2) is one of the most intensively studied members. CADM1 participates in intercellular adhesion and plays a role in synapse formation in the nervous system.

Meanwhile, multiple studies have found that abnormal CADM1 expression is associated with various tumors; particularly in lung cancer, decreased CADM1 expression correlates with reduced cell adhesion capacity and enhanced tumor invasion ^[13].

CADM2 is predominantly expressed in the nervous system and is believed to participate in information exchange between nerve cells and maintenance of neural functions ^[14]. CADM3 and CADM4 are also involved in cell junctions within neural tissues and have received attention in some tumor studies.

Overall, CADM members embody the characteristics of NECTIN-like molecules: they do not exist merely as structural adhesion molecules but influence tissue function by regulating intercellular communication. However, compared with Nectin-4 and CD155, the CADM family has not yet established a clear clinical translation direction.

3.6 Necl-5: A Viral Receptor, Cell Migration Regulator, and Core Molecule in Tumor Immunity

Necl-5 (CD155) is one of the most functionally complex members of the NECTIN family.

CD155 was first discovered as the poliovirus receptor. Viruses can exploit CD155 to mediate cell entry, making it a classic subject of virus-host interaction research ^[15].

Subsequent studies found that CD155 is also involved in normal cell migration, proliferation, and cytoskeletal regulation. During cell migration, CD155 can influence cell movement-related signals, and in various tumors, elevated CD155 expression is associated with enhanced invasiveness ^[4].

In recent years, the hottest research area for CD155 has been tumor immunity. CD155 can bind multiple immune receptors, including TIGIT, CD226, and CD96. Among these, CD226 generally mediates immune activation, TIGIT has a clearly defined immunosuppressive effect, while CD96 also exerts immunosuppressive functions in most contexts, although its specific mechanisms are still under intensive investigation ^[16].

Because the same ligand simultaneously participates in both activating and inhibitory signal regulation, CD155 has become a critical balancing node in tumor immunity. When tumor cells highly express CD155, they may enhance inhibitory pathway signals such as TIGIT, restricting immune cell function.

4. NECTIN Family Research Products

Research on the NECTIN family involves protein-protein interactions, cellular signaling, and disease mechanisms, requiring diverse experimental tools. CUSABIO provides a comprehensive portfolio of research products covering NECTIN family members, applicable to protein-protein interaction analysis, expression detection, receptor binding functional validation, and other scenarios, supporting basic scientific research and drug development.