The cadherin superfamily is made of transmembrane glycopr...

The cadherin superfamily is made of transmembrane glycoproteins involved in calcium-dependent cell-cell adhesion and cell-cell recognition (reviewed in Gul et al. 2015). The human type I subfamily of classical cadherins includes CDH1 (E-cadherin), CDH2 (N-cadherin), CDH3 (P-cadherin), CDH4 (R-cadherin), and CDH15 (M-cadherin) (reviewed in Gul et al. 2015). Like other classical cadherins, Type I cadherins possess five extracellular cadherin domains (EC1-5), which drive cell-cell adhesion through formation of trans-dimers, usually trans-homodimers (also known as homotypic dimers), between two identical cadherin molecules expressed on plasma membranes on two adjacent cells (reviewed in Brasch et al. 2012). Type I classical cadherins contain a conserved tryptophan residue at the second position of their EC1 domain, while Type II cadherins contain two conserved tryptophan residues at positions 2 and 4 of their EC1 domain (reviewed in Brasch et al. 2012). These tryptophan residues directly participate in formation of cadherin trans-dimers (reviewed in Brasch et al. 2012). Type I cadherin also contain a conserved diproline motif, with two proline residues at position 5 and 6 of their EC1 domain (reviewed in Brasch et al. 2012). The diproline motif increases the specificity of Type I cadherins for binding identical cadherin molecules, thus favoring formation of homotypic dimers, while Type II cadherins also engage in formation of heterotypic dimers (reviewed in Brasch et al. 2012).

Homotypic trans-dimers of CDH1, also known as epithelial cadherin, are a central complex in adherens junctions of polarized epithelia (reviewed in Zhang et al. 2023). Loss-of-function missense mutations in CDH1 are an underlying cause of about 30% of cases of hereditary diffuse gastric cancer (HDGC), and a polymorphism in CDH1 gene promoter has also been associated with increased gastric cancer risk (reviewed in Li et al. 2014). CDH1 is frequently downregulated in tumors of epithelial origin and is considered to be a tumor suppressor gene (reviewed in Bruner and Derksen 2018). Loss of CDH1 expression promotes epithelial-to-mesenchymal transition (EMT), implicated in tumor invasiveness (reviewed in Bruner and Derksen 2018).