Crossroads of integrins and cadherins in epithelia and stroma remodeling

Abstract

Adhesion events mediated by cadherin and integrin adhesion receptors have fundamental roles in the maintenance of the physiological balance of epithelial tissues, and it is well established that perturbations in their normal functional activity and/or changes in their expression are associated with tumorigenesis. Over the last decades, increasing evidence of a dynamic collaborative interaction between these complexes through their shared interactions with cytoskeletal proteins and common signaling pathways has emerged not only as an important regulator of several aspects of epithelial cell behavior, but also as a coordinated adhesion module that senses and transmits signals from and to the epithelia surrounding microenvironment. The tight regulation of their crosstalk is particularly important during epithelial remodeling events that normally take place during morphogenesis and tissue repair, and when defective it leads to cell transformation and aggravated responses of the tumor microenvironment that contribute to tumorigenesis. In this review we highlight some of the interactions that regulate their crosstalk and how this could be implicated in regulating signals across epithelial tissues to sustain homeostasis.

Figure 1. Complexes implicated in cell-cell and cell-matrix adhesion. Cell-cell adhesion complexes: in blue, tight junctions (TJs) composed by the transmembrane proteins occludins, claudins (1–24), junctional adhesion molecule (JAM A–C), and the cytoplasmic proteins zonula occludens (ZO 1–3), the cell polarity protein partitioning defective-3 (PAR3), MUPP1 and MAG1. In green, adherens junctions (AJs) composed by Cadherin and Nectin complexes. The transmembrane protein E-cadherin binds to the cytoplasmic proteins p120 catenin, α-catenin and β-catenin, whereas Nectin binds to afadin. In orange, desmosomes are constituted by the transmembrane proteins desmoglein (DSG 1–4) and desmocollin (DSC 1–3), and the cytoplasmic proteins plakoglobin (JUP), plakophilins (PKP 1–3) and desmoplakin (DSP) that anchor to intermediate filaments. Cell-matrix adhesion complexes: in red, the hemidesmosomes (HD), formed by the transmembrane α- and β-integrins and the cytoplasmic proteins BP180, BO230 and plectin. In purple, the focal adhesion complex (FAs), composed by the transmembrane α- and β-integrins and cytoplasmic scaffolding proteins that associate to the actin cytoskeleton.

Figure 2. A reciprocal and coordinated regulation of FAs and AJs in epithelial cells is involved in the crosstalk between epithelia and stroma. FAs and AJs share downstream signaling molecules, including Rho GTPases and Src, and interactions with actomyosin cytoskeleton, which contribute to the coordination of their adhesive network. Whereas FAs assembly is related to a strengthening of AJ-mediated adhesion, AJs disassembly is related to an increase of FAs-mediated adhesion. During tumorigenesis the coordinated crosstalk between FAs and AJs in epithelial cells is impaired, and may result in the chronic activation of the stroma (e.g., secretion of soluble factors, cytokines, chemokines, MMPs, and changes in ECM composition). These can generate perpetuating signaling loops without a clear endpoint that, if unresolved, may lead to further epithelial transformation with gain of migratory and invasive characteristics. In this figure, some specific signaling adhesive modules are shown using color-coded annotations as well as their points of convergence.