About this Research Topic
Sensing of microenvironmental cues is a fundamental aspect of living cells as it determines their fate under the constant and evolving changes of their surroundings. Failure to properly read external signals leads to the cell’s demise and thus there is no room for errors. Within the cellular microenvironment, external signals, soluble and insoluble, emanate from multiple sources, which are sorted and analyzed by specific receptor systems in charge of interpreting and decoding the signals to activate the proper intracellular effectors. This is an extraordinary task considering the complex and dynamic nature of the signaling universe that drive cell behavior and ultimately the survival of the organism.
Among the prime signaling systems that influence cell behavior, the extracellular matrix (ECM) occupies a prominent place. The ECM is an insoluble multiprotein network that completely surrounds cells in a three-dimensional environment in which cells exercise their physiological functions. Signals emanated from ECM components are both mechanical and non-mechanical, which are decoded by specific receptor systems localized at the cell surface. In turn, these receptors activate downstream effectors that regulate multiple cellular activities including cell adhesion, migration, proliferation, and plasticity to mention just a few. Thus, these receptor systems are crucial for the physiological functioning of organisms. However, dysregulation of ECM-cell interactions is a well-established pathogenic insult in many diseases, and thus a source of potential targets for therapeutic intervention. This goal requires a thorough understanding of receptor function in normal and pathological processes but also of their structural features and their interacting partners in various biological settings. There is also a fundamental need to understand how different ECM receptor families coordinate their action in response to distinct ECM components and their biomechanical status, so that the cellular outcome is compatible and consistent with normal function. The ECM receptors are usually families of transmembrane multidomain glycoproteins that recognize specific components of the ECM through their extracellular domains while their intracellular portions establish molecular connections with components of the cytoskeletal system or with other surface and intracellular proteins that help relay ECM-initiated signaling.
This Research Topic focusses on the two major receptor families for ECM, namely the integrins and the discoidin domain receptors (DDRs), both displaying distinct structural features and mechanisms of action, yet their repertoire of ECM collagen ligands can overlap. Integrins and DDRs are both transmembrane proteins that transmit ECM signals through protein-protein interactions (integrin) or through the activation of intrinsic kinase activity (DDRs), which demonstrate the evolution of ECM-initiated signaling aimed at obtaining ECM-sensing proteins that encompass different mechanisms of action. Integrins and DDRs, due to their intrinsic role as translators of the ECM-mediated and/or originated stimuli, are considered key pharmacological targets modulating cell autonomous responses contributing to several key pathophysiological processes. Genetic manipulation and pharmacological modulation of those targets have in fact revealed their relevance in slowing down cancer and fibrosis progression in different organs.
The aim of this Research Topic is to understand the ECM receptors function in normal and pathological processes, their structural features and their interacting partners in various biological settings. Pharmacological evidence and pharmacological tools targeting the ECM receptors will also be discussed. We welcome Original Research and Review articles that discuss the regulation of these ECM-cell systems. We also welcome articles that describe potential targets for therapeutic intervention.
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