Cells can detect and react to the biophysical properties of the extracellular environment through integrin-based adhesion sites and adapt to the extracellular milieu in a process called mechanotransduction. evolved by developing and diversifying genes involved in cell differentiation, cellCcell communication, and cell adhesion (Rokas, 2008). Cell adhesion to the ECM and to neighboring cells allows cells of different lineages to interact at the organ level by facilitating the exchange of biochemical and biophysical information. The ECM of the metazoan is mainly composed of fibrous proteins (e.g., collagens and elastin) that confer the ECM with tensile strength and elasticity, proteoglycans (e.g., perlecan and hyaluronan) that allow interfibrillar slippage under tensile loads and thus confer the ECM with viscosity, and multiadhesive glycoproteins (e.g., fibronectin and laminins) that bind proteoglycans and collagen fibers (Mouw et al., 2014). ECM proteins are recognized by specific cell surface receptors such as integrins, syndecans, CD44, and dystroglycan. ECM receptors induce signaling pathways and facilitate the assembly of different ECM components into sheet-like fibrous structures (basement membranes) or seemingly chaotic meshworks of fibrils and fibers (connective tissue) whose biochemical composition, compliance, and geometric and topographic features in nanometer to micrometer scale vary MK-2206 2HCl kinase inhibitor and correlate with tissue-specific physiological functions (Gasiorowski et al., KLF4 2013). The complex biochemical and biophysical characteristics of the ECM contain a wealth of biological information that, in concert with soluble growth factors that are often immobilized within the ECM, exerts a profound impact on many cellular behaviors, including migration, proliferation, and differentiation. To detect and interpret the biological information in the ECM, cells adhere and transduce myosin-generated traction forces to the ECM via integrin-based adhesions and elicit a series of dynamic signaling events that are jointly termed mechanotransduction (Hoffman et al., 2011). Integrin-mediated mechanotransduction commences with force transmission between cells and the ECM (termed mechanotransmission), a process that occurs across the mechanosensitive, integrin-based adhesions. The mechanical load on the adhesion sites leads to force-induced functionalities, such as changes in protein conformation or enzymatic reactions (e.g., kinase activities) that in turn induce biochemical signals (termed mechanosignaling). Finally, the MK-2206 2HCl kinase inhibitor mechanically induced biochemical signals generate appropriate cellular responses that adapt to physiological processes (e.g., polarity, migration, differentiation, and survival) accordingly. In this review, we introduce the main concepts of integrin-mediated mechanotransduction, summarize recent progress on the underlying biophysical principles and the in vivo functional significance, and discuss how the viscoelasticity of the ECM influences integrin-mediated mechanotransduction and how its dysregulation impacts on cancer progression. Structure of integrin-based adhesions Integrins, which connect the ECM with intracellular actin cytoskeleton and thereby mechanically integrate the extracellular and intracellular compartments, are heterodimeric transmembrane receptors composed of and subunits. There are 24 different integrin receptors in mammals, each recognizing a specific set of ECM ligands (Hynes, 2002). Integrin-mediated adhesion starts with conformational changes in the integrin ectodomain (integrin activation) that shift integrins from a low- to high-affinity state for ligand binding (Luo et al., 2007; Su et al., 2016). Kindlin and talin bind integrin cytoplasmic tails (with the exception of 4 integrin tails; de Pereda et al., 2009) and promote integrin activation (Calderwood et al., 2013). Upon ligand binding, integrins recruit numerous proteins to their short cytoplasmic tails, resulting in the assembly of various MK-2206 2HCl kinase inhibitor adhesion structures that differ in their morphology and subcellular localization as well as in their protein composition and mechanical properties (Schiller and F?ssler, 2013). The first adhesion structure assembles at the leading edge of cell protrusions by nucleating three MK-2206 2HCl kinase inhibitor to six integrins interspaced by less than 70 nm into short-lived nascent adhesions (NAs; Fig. 1; Cavalcanti-Adam et al., 2007; Hu et al., 2007; Bachir et al., 2014). The mechanism by which integrins first assemble is unclear. Apart from their signaling function, NAs are able to transmit the retrograde pushing forces from the polymerizing branched actin network in membrane protrusions to the ECM via mechanosensitive proteins such as talin and vinculin. The assembly of NAs between lamellipodium and lamellum MK-2206 2HCl kinase inhibitor correlates with the switch from a fast to a slow actin retrograde flow rate caused by the transient coupling of integrins.