Molecular Crosstalk between Integrins and Cadherins: Do Reactive Oxygen Species Set the Talk?

Abstract

The coordinate modulation of the cellular functions of cadherins and integrins plays an essential role in fundamental physiological and pathological processes, including morphogenesis, tissue differentiation and renewal, wound healing, immune surveillance, inflammatory response, tumor progression, and metastasis. However, the molecular mechanisms underlying the fine-tuned functional communication between cadherins and integrins are still elusive. This paper focuses on recent findings towards the involvement of reactive oxygen species (ROS) in the regulation of cell adhesion and signal transduction functions of integrins and cadherins, pointing to ROS as emerging strong candidates for modulating the molecular crosstalk between cell-matrix and cell-cell adhesion receptors.

Figure 1

Schematic representation of ROS metabolism and signaling. The superoxide anion (O₂ ^∙−) is a key determinant of oxidative effects as well as the precursor of all other major reactive oxygen species, including hydroxyl radical (^∙OH), hydrogen peroxide (H₂O₂), and peroxynitrite (OONO⁻). It is generated constitutively as by-product of oxidative metabolism, as well as upon stimuli triggering the activation of oxidative enzymes, including NADPH oxidases, xanthine oxidases, cytochrome P450 monooxygenases, uncoupled NO synthase (NOS), myeloperoxidases, lipoxygenases (LOX), and cyclooxygenases (COX). Conversely, O₂ ^∙− is removed by superoxide dismutase (SOD) enzymes, which catalyze the dismutation of O₂ ^∙− into H₂O₂ and O₂. In turn, H₂O₂ is reduced to H₂O by the catalase (CAT) and glutathione peroxidase (GPX) enzymes. At physiologic concentrations, ROS are endowed with essential signaling properties, being involved in the redox-dependent regulation of multiple signal transduction pathways to fulfill a wide range of essential biological processes, including cell adhesion, migration, proliferation, differentiation, and survival. However, at high levels, ROS exert very damaging effects through oxidative stress. H-W: Haber-Weiss reaction; NO: nitric oxide.

Figure 2

ROS mediate integrin outside-in signaling. Integrin engagement with extracellular matrix (ECM) proteins triggers a transient and localized burst of ROS, either independently or in cooperation with growth factor receptors (GFR), which is essential to the proper transduction of outside-in signaling pathways. The small GTPase Rac1 acts as a crucial upstream regulator of ROS production, orchestrating integrin outside-in signaling-mediated changes in mitochondrial metabolic/redox function, and activation of distinct oxidases, including NADPH-oxidases (NOX), 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2). The signaling properties of integrin-induced ROS are largely due to the reversible oxidation of specific subsets of redox-sensitive proteins, including oxidative inhibition of PTPs, and activation of PTKs, RPTKs, small GTPases of the Ras and Rho families, and transcription factors (TF) such as AP-1 and NF-κB.

Figure 3

ROS modulate cadherin-mediated cell-cell junctions. Rac1-induced ROS may function as signaling molecules to disrupt cadherin-based cell-cell adhesion through either inhibition or activation of regulatory tyrosine phosphatases and kinases, respectively, as well as by localized activation of IQGAP and small GTPases, leading to various biological responses, including cell migration and proliferation.

Figure 4

ROS in the crosstalk between integrins and cadherins. ROS generated by integrin activation may influence cadherin adhesive functions by various mechanisms, including inhibition of PTPs and/or activation of PTKs, RPTKs, and IQGAP acting at adherens junctions, as well as spatiotemporal modulation of the activity of redox-sensitive small GTPases and signaling endosomes.