Integrins are the major family of adhesion molecules that mediate cell adhesion to the extracellular matrix. They are essential for embryonic development and influence numerous diseases, including inflammation, cancer cell invasion and metastasis. In this Perspective, we discuss the current understanding of how talin, kindlin and mechanical forces regulate integrin affinity and avidity, and how integrin inactivators function in this framework. In this Perspective, Fassler and co-authors describe current models of how integrin adhesion molecules are activated and stabilised, and the importance of forces in this process.

Integrin activation by talin, kindlin and mechanical forces

Integrins are heterodimeric cell surface receptors ensuring the mechanical connection between cells and the extracellular matrix. In addition to the anchorage of cells to the extracellular matrix, these receptors have critical functions in intracellular signaling, but are also taking center stage in many physiological and pathological conditions. In this review, we provide some historical, structural, and physiological notes so that the diverse functions of these receptors can be appreciated and put into the context of the emerging field of mechanobiology. We propose that the exciting journey of the exploration of these receptors will continue for at least another new generation of researchers.

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Cell Adhesion by Integrins.

https://www.research.manchester.ac.uk/portal/files/76014124/COCEBI_2018_4_Revision_1_V01.pdf

Signal transduction via integrin adhesion complexes.

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.

/pdf/platelet-integrin-aiibb3-signal-transduction-regulation-and-1cmbbd9oqk.pdf

Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting

Cell spreading requires the coupling of actin-driven membrane protrusion and integrin-mediated adhesion to the extracellular matrix. The integrin-activating adaptor protein kindlin-2 plays a central role for cell adhesion and membrane protrusion by directly binding and recruiting paxillin to nascent adhesions. Here, we report that kindlin-2 has a dual role during initial cell spreading: it binds paxillin via the pleckstrin homology and F0 domains to activate Rac1, and it directly associates with the Arp2/3 complex to induce Rac1-mediated membrane protrusions. Consistently, abrogation of kindlin-2 binding to Arp2/3 impairs lamellipodia formation and cell spreading. Our findings identify kindlin-2 as a key protein that couples cell adhesion by activating integrins and the induction of membrane protrusions by activating Rac1 and supplying Rac1 with the Arp2/3 complex.

/pdf/kindlin-2-recruits-paxillin-and-arp2-3-to-promote-membrane-4mbz7hg55f.pdf

Kindlin-2 recruits paxillin and Arp2/3 to promote membrane protrusions during initial cell spreading.

Kindlins and talins are integrin-binding proteins that are critically involved in integrin activation, an essential process for many fundamental cellular activities including cell-matrix adhesion, migration, and proliferation. As FERM-domain–containing proteins, talins and kindlins, respectively, bind different regions of β-integrin cytoplasmic tails. However, compared with the extensively studied talin, little is known about how kindlins specifically interact with integrins and synergistically enhance their activation by talins. Here, we determined crystal structures of kindlin2 in the apo-form and the β1- and β3-integrin bound forms. The apo-structure shows an overall architecture distinct from talins. The complex structures reveal a unique integrin recognition mode of kindlins, which combines two binding motifs to provide specificity that is essential for integrin activation and signaling. Strikingly, our structures uncover an unexpected dimer formation of kindlins. Interrupting dimer formation impairs kindlin-mediated integrin activation. Collectively, the structural, biochemical, and cellular results provide mechanistic explanations that account for the effects of kindlins on integrin activation as well as for how kindlin mutations found in patients with Kindler syndrome and leukocyte-adhesion deficiency may impact integrin-mediated processes.

https://www.pnas.org/content/pnas/114/35/9349.full.pdf

Structural basis of kindlin-mediated integrin recognition and activation

Formation of cell-extracellular matrix adhesion requires assembly of the transmembrane receptor integrins and their intracellular activators, kindlin and talin proteins in minutes. The mechanisms governing the rapid formation and dynamics of the adhesion remain enigmatic. Here, we reported that the dimerized-kindlin2 underwent phase separation with clustered-integrin in solution and on lipid bilayer. The kindlin2/integrin condensate can further enrich other components for the adhesion complex assembly. The full-length structure of kindlin2 was solved and revealed that the kindlin2 dimers can further pack with each other to form a higher oligomer. Disrupting the intermolecular interaction between the kindlin2 dimer inhibits the phase formation on 2D membrane in vitro and impaired the adhesion formation, integrin activation, and cell spreading in cultured cells. We also determined the full-length structure of kindlin2 in its monomeric conformation. Structural analysis and biochemical characterization indicate that the interdomain interaction control the monomer-dimer transition of kindlin2, providing a regulation mechanism of the kindlin2-mediated phase separation. Our findings not only provide a mechanistic explanation for the formation and dynamic regulation of the integrin-based adhesion, but also shed light on understanding of how the clustered receptors participate in assembly of the functional membrane domains via phase separation.

https://biorxiv.org/content/10.1101/2020.07.10.197400v1.full.pdf

Kindlin2-mediated phase separation underlies integrin adhesion formation

It has been predicted that China has about 80 billion tons of oil equivalent of natural gas hydrate resources in its sea. China has conducted at least six drilling and two trial exploitations in the South China Sea, achieving good results. However, these achievements do not necessarily mean that the research area can support commercial exploitation. Only when the natural gas hydrate resources in the research area reach a certain scale will it be valuable for commercial exploitation. A reliable quantitative prediction method is necessary to clarify the scale of gas hydrate in the research area. However, the classical Wood method’s application to the prediction of suspended hydrate saturation in the Shenhu maritime area of China results in a large prediction error; the analysis shows that an unreliable measurement of reservoir parameters is the main reason for the large prediction error. In order to clarify the influence of reservoir parameters, this paper—by analyzing the measurement sources of the parameters of reservoir parameters, firstly indicates that the inaccurate measurement of three reservoir parameters—matrix composition, porosity, and density—is the main cause of prediction error. Then, using the design of different reservoir parameter measurement schemes to conduct comparative analysis, this paper points out that unreliable porosity and density measurement may lead to large prediction errors, while unreliable measurements of matrix composition have a relatively small impact on prediction accuracy. Further analysis shows that the absolute value of the prediction error caused by uncertainty in synthetic reservoir parameter measurement is sometimes larger than the sum of the absolute prediction error caused by the single parameter measurement uncertainty. In addressing the problem of large prediction errors caused by the inaccurate measurement of reservoir parameters, this paper proposes a hydrate saturation prediction method based on non-hydrate correction—called the “Wood-Bao method”. Simulation and actual data studies show that the prediction effect of this method is superior to that of the Wood method.

Research on a hydrate saturation prediction method based on an analysis of factors that influence the prediction accuracy of sea area hydrate saturation

Huadong Li

Papers

Structural basis of kindlin-mediated integrin recognition and activation

Kindlin2-mediated phase separation underlies integrin adhesion formation

Research on a hydrate saturation prediction method based on an analysis of factors that influence the prediction accuracy of sea area hydrate saturation