The extracellular matrix–myosin pathway in mechanotransduction: from molecule to tissue

Abstract

Mechanotransduction via the extracellular matrix (ECM)-myosin pathway is involved in determining cell morphology during development and in coupling external transient mechanical stimuli to the reorganization of the cytoskeleton. Here, we present a review on the molecular mechanisms involved in this pathway and how they influence cellular development and organization. We investigate key proteins involved in the ECM-myosin pathway and discuss how specific binding events and conformational changes under force are related to mechanical signaling. We connect these molecular mechanisms with observed morphological changes at the cellular and organism level. Finally, we propose a model encompassing the biomechanical signals along the ECM-myosin pathway and how it could be involved in cell adhesion, cell migration, and tissue architecture.

Fibrillar Collagen Type I Participates in the Survival and Aggregation of Primary Hepatocytes Cultured on Soft Hydrogels

“…By contrast, actin cytoskeleton was reorganized into stress fibers in mesenchymal-like hepatocytes that had been cultured on stiff hydrogels after 72 h of culture (Figure 2A). The formation of stress fibers, associated with cell spreading and contractility [50], could explain the increase in cell area in hepatocytes cultured on stiff PAA HGs (Figure 1A). A 3D projection built from confocal microscopy images showed clearly the formation of intercellular partial ducts that resembled hepatic canaliculi in hepatocytes cultured on 1 kPa PAA HGs (Figure 2C).…”

“…Cells respond to external mechanical properties by transducing them into biochemical mechanisms; all these molecular mechanisms are known as mechanotransduction pathways [46][47][48][49]. Despite the complexity of mechanotransduction mechanisms, actin cytoskeleton dynamics is involved in most of them, due to the fact that external stress is transmitted as internal tensile forces that totally depend on the actomyosin apparatus: actin fibers and force-generating proteins, myosins [50][51][52]. There is an increasing number of scientific reports demonstrating that in the liver too, hepatocytes and non-parenchymal cells are regulated by external mechanics [26,37,53,54].…”

Does protein unfolding play a functional role in vivo?

“…Talin is the mechanical computer of cell–ECM interaction, as it can accept as input mechanical forces and interaction with other proteins to produce as output direct and cross‐connections [78,79]. These connections drive actin filaments at the focal adhesion site to balance the forces developed between cells and their matrices [78,79]. (a) Fine‐tuned quantized response: Talin has a FERM head and 13 rod domains.…”

“…Integrins are a protein family of heterodimers with an α‐ and a β‐subunit [75,76], which upon activation produce a conformational change of ~ 7.5 nm, one of the largest known changes in biological systems [77]. Integrins are linked to actin through an adaptor protein, talin, which recruits additional cytoplasmic effectors that play a role in the assembly of adhesive complex [78,79]. Talin acts as a mechanosensor through conformational changes of its FERM head and 13 rod domains.…”

Force-Directed “Mechanointeractome” of Talin–Integrin

“…13,107−113 The structural changes of integrin during its interaction with ligands primarily take place in the transmembrane (TM) and extracellular regions. The crystal structure of the αIIbβ3 F3, R2, R3, R8, R11 unfolds F3 to induce integrin activation DLC1 62,63 R8 acts as a tumor suppressor, weakens myosin activation and migration α-synemin 64 R8 integrates mechanical stress and maintain structural integrity in eukaryotic cells KANK1−4 54 R7 blocks talin−actomyosin interaction, regulates cell migration and polarity FAK 65 F3 regulates adhesion assembly, cell motility, and adhesion turnover layilin 66 F3 assists in cell adhesion along with hyaluronan in ECM Gα13 35 F3 removes talin's autoinhibited state TIAM 1 67 F3 activates Rac1 and induces cell spreading PIP15Kγ90 68 F3 synthesizes PIP2 in talin-induced integrin activation moesin 69,70 R11, R13 regulates cell migration signaling in cellular protrusion integrin subtype shows that TM domain separation occurs during the active state, whereas in αVβ3, those TM domains remain separated in its inactive form. During these interactions, the ectodomain changes its conformation from a thermodynamic inactive state to a rare active state.…”