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Review
. 2016 Nov 21;215(4):445-456.
doi: 10.1083/jcb.201609037. Epub 2016 Nov 8.

Integrin-mediated mechanotransduction

Zhiqi Sun  1 , Shengzhen S Guo  2 , Reinhard Fässler  2
Affiliations
Review

Integrin-mediated mechanotransduction

Zhiqi Sun et al. J Cell Biol. .

Abstract

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. At these adhesion sites, integrins connect the extracellular matrix (ECM) with the F-actin cytoskeleton and transduce mechanical forces generated by the actin retrograde flow and myosin II to the ECM through mechanosensitive focal adhesion proteins that are collectively termed the "molecular clutch." The transmission of forces across integrin-based adhesions establishes a mechanical reciprocity between the viscoelasticity of the ECM and the cellular tension. During mechanotransduction, force allosterically alters the functions of mechanosensitive proteins within adhesions to elicit biochemical signals that regulate both rapid responses in cellular mechanics and long-term changes in gene expression. Integrin-mediated mechanotransduction plays important roles in development and tissue homeostasis, and its dysregulation is often associated with diseases.

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Figures

Figure 1.
Figure 1.
Model of a migrating cell containing diverse integrin-based adhesion structures that transmit different levels of traction forces. Nascent adhesions (NAs) emerge at the leading edge of cell protrusions by nucleating multiple ligand-bond integrins that have been activated by talin and kindlin. Adhesome proteins such as vinculin are subsequently recruited to adhesion sites via talin in a tension-dependent manner or via paxillin in a tension-independent manner. NAs are dynamically coupled to the polymerizing branched actin network through proteins of the molecular clutch such as talin and vinculin, which convert the retrograde movement of polymerizing branched actin network into a protrusive force at the leading edge membrane and rearward traction force on the ECM. A small number of NAs matures into large focal adhesions (FAs) along actomyosin bundles in the lamella. Within mature FAs, the molecular clutch becomes strongly engaged by F-actin binding to the talin ABS2 and ABS3 sites and vinculin binding to VBS where high traction forces are transmitted across integrins, leading to catch bond formation between integrin and ligand. Behind the lamella, Kank2 is recruited to the FA belt, where it maintains talin in its active integrin-bond state and at the same time diminishes F-actin binding to talin ABS2. Consequently, Kank2 decreases force transmission leading to the slip bond formation between integrin and its ligand and the translocation of FA belt-localized β1 integrins into fibrillar (or central) adhesions. At the rear end of migrating cells, trailing edge FAs may apply such high traction forces that detach the cell rear, probably together with integrin-bound ECM fragments.
Figure 2.
Figure 2.
Talin-based molecular clutch mediates mechanotransmission. (A) Domain organization of talin. The N-terminal talin head domain (THD) is an atypical FERM domain composed of F0, F1, F2, and F3 subdomains containing an integrin tail–binding site (IBS1). THD is linked to the talin rod domain via a flexible linker of ∼80 amino acids. The talin rod domain contains 13 helix bundles (R1–R13) and a dimerization domain (DD) and a second, underinvestigated integrin tail-binding site (IBS2). The IBS1, IBS2, three actin-binding sites (ABS1–3), two critical vinculin-binding sites (VBSs) in the R3 and R8 domains, and binding sites for RIAM, Kank2, and DLC1 are shown. The remaining VBSs are not depicted. (B) Model depicting the mechanical response of the molecular clutch and integrin–ligand bonds on the soft or rigid ECM in the presence or absence of Kank2. On soft substrates, the slow loading rates fail to induce talin unfolding and vinculin recruitment before the slip bond between integrin and the ligand ruptures under low force. In contrast, on rigid substrate, high loading rates induce vinculin-dependent clutch reinforcement, catch bond formation, and high force transmission. Kank2 interferes with F-actin binding to the talin ABS2, leading to reduced force transmission across talin as well as a diminished activation of VBSs. Consequently, Kank2 abrogates the clutch reinforcement and induces frequent ruptures of the slip bond between integrin and ligand even on rigid substrates.
Figure 3.
Figure 3.
Glycocalyx around integrin–ligand complexes promotes integrin–ligand binding and clustering. The glycocalyx is a layer of glycoprotein–polysaccharide complexes on the cell surface that exerts electrosteric and osmotic repulsion to the ECM. Because the height of the glycocalyx exceeds that of the active integrins, the glycocalyx must be mechanically compressed around integrin–ligand complexes (indicated as blue arrows). Ligand-bound integrins within the compressed glycocalyx reciprocally sense the pulling force that promotes catch-bond formation and mechanotransduction. Glycocalyx-embedded integrin–ligand complexes shorten the distance between the plasma membrane and the ECM, which increases the probability of integrin activation and clustering around existing integrin-based adhesion sites in a kinetic trap-like manner. Talin is immobilized by actomyosin bundles within FAs, where it captures and activates integrins that enter the kinetic trap.
Figure 4.
Figure 4.
Molecular tension sensors are used to measure the forces sensed by mechanosensitive proteins. (A) Models of the different types of molecular tension sensors (MTSs). A typical MTS is composed of a FRET pair (or fluorophore-quencher pair) connected by a spring-like linker that can be extended by force. Three types of MTSs have been invented: the peptide-based MTS uses engineered tension-sensitive peptide as the linker and can be genetically encoded into intracellular proteins, the DNA-based digital MTS unwinds its hairpin structure and changes fluorescence intensity when force is above a defined threshold and is used to determine the lower limits of mechanical stress, and the DNA-based rupturable MTS is irreversibly ruptured by forces above defined thresholds and is used to approach the upper limits of forces transmitted by cell surface receptors. (B) Limitation of the bulk measurement in an MTS experiment. Because of the spatial resolution, current MTS measurements calculate forces as the mean mechanical stress of all MTS probes within each pixel. Such a measurement is strongly influenced by the background of unengaged MTS probes and the variation of forces sensed by each individual MTS probe.
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