8.A.204. The Cadherin (CDH) Family
Cadherins are calcium-dependent cell adhesion proteins (Meigs et al. 2002). They preferentially interact with themselves in a homophilic manner to connect cells; cadherins may contribute to the sorting of heterogeneous cell types. CDH1 (E-canherin) is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells (Meigs et al. 2002). They have a potent invasive suppressor role and are ligands for integrin alpha-E/beta-7. E-Cad/CTF2 promotes non-amyloidogenic degradation of Abeta precursors and has a strong inhibitory effect on APP C99 and C83 production. It serves as a receptor for Listeria monocytogenes; internalin A (InlA) binds to this protein and promotes uptake of the bacteria. Desmosomes are protein assemblies that mediate cell-cell adhesion and are prevalent in tissues under mechanical stress, such as heart and epithelial tissues (Pasani et al. 2023). These authors characterized the molecular architecture of the desmosomal outer dense plaque (ODP), and a validated model of the desmosomal ODP provided mechanistic insight into the function and assembly of desmosomes in normal and disease states (Pasani et al. 2023).
The function and structure of the mammalian epithelial cell layer is maintained by distinct intercellular adhesion complexes including adherens junctions (AJs), tight junctions, and desmosomes. The AJ is most integral for stabilizing cell-cell adhesion and conserving the structural integrity of epithelial tissues. AJs are comprised of the transmembrane protein E-cadherin and cytoplasmic catenin cofactors (alpha, beta, gamma, and p120-catenin) (Lessey et al. 2022). One organ where malfunction of AJ is a major contributor to disease states is the mammalian intestine. In the intestine, cell-cell adhesion complexes work synergistically to maintain structural integrity and homeostasis of the epithelium and prevent its malfunction. Consequently, when AJ integrity is compromised in the intestinal epithelium, the ensuing homeostatic disruption leads to diseases such as inflammatory bowel disease and colorectal carcinoma. In addition to their function at the plasma membrane, protein components of AJs have nuclear functions and are implicated in regulating gene expression and intracellular signaling. Within the nucleus, AJ proteins interact with transcription factors such as TCF/LEF and Kaiso (ZBTB33), which converge on the canonical Wnt signaling pathway. The multifaceted nature of AJ proteins highlights their complexity in modulating homeostasis and emphasizes the importance of their subcellular localization and expression in the mammalian intestine (Lessey et al. 2022).