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Journal ArticleDOI

Talins and kindlins: partners in integrin-mediated adhesion

TL;DR: New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell–matrix junctions.
Abstract: Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling.

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Citations
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Journal ArticleDOI
TL;DR: Sun, Guo, and Fässler review the function and regulation of integrin-mediated mechanotransduction and discuss how its dysregulation impacts cancer progession.
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.

667 citations


Cites background from "Talins and kindlins: partners in in..."

  • ...The talin rod domain contains two additional F-actin–binding sites (ABS2 and ABS3), 11 vinculin-binding sites (VBSs), and binding sites for regulatory proteins, including RIAM (Rap1–GTP-interacting adapter molecule), Kank (KN motif and ankyrin repeat domains) family proteins (whose functions are discussed in the following paragraphs), and the Rho GTPase activating protein DLC1 (deleted in liver cancer 1; Calderwood et al., 2013; Sun et al., 2016)....

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  • ...…including RIAM (Rap1–GTP-interacting adapter molecule), Kank (KN motif and ankyrin repeat domains) family proteins (whose functions are discussed in the following paragraphs), and the Rho GTPase activating protein DLC1 (deleted in liver cancer 1; Calderwood et al., 2013; Sun et al., 2016)....

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Journal ArticleDOI
23 Jul 2020-Cell
TL;DR: To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), single-cell RNA sequencing with spatial transcriptomics and multiplexed ion beam imaging from a series of human cSCCs and matched normal skin were combined.

451 citations


Cites background from "Talins and kindlins: partners in in..."

  • ...The protein products of ITGB1, CD151, and FERMT1 physically interact at the cell surface to mediate integrin signaling (Calderwood et al., 2013; Hemler, 2005)....

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Journal ArticleDOI
TL;DR: The current understanding of how talin, kindlin and mechanical forces regulate integrin affinity and avidity is discussed, and how integrin inactivators function in this framework.
Abstract: 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.

331 citations

Journal ArticleDOI
TL;DR: The cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis are focused on.

304 citations

Journal ArticleDOI
TL;DR: The results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.
Abstract: Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell–extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.

288 citations

References
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Journal ArticleDOI
20 Sep 2002-Cell
TL;DR: Current structural and cell biological data suggest models for how integrins transmit signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways.

8,275 citations

Journal ArticleDOI
30 Jan 2009-Science
TL;DR: It is shown that mechanical stretching of single cytoplasmic proteins can activate binding of other molecules and molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system.
Abstract: The molecular mechanism by which a mechanical stimulus is translated into a chemical response in biological systems is still unclear. We show that mechanical stretching of single cytoplasmic proteins can activate binding of other molecules. We used magnetic tweezers, total internal reflection fluorescence, and atomic force microscopy to investigate the effect of force on the interaction between talin, a protein that links liganded membrane integrins to the cytoskeleton, and vinculin, a focal adhesion protein that is activated by talin binding, leading to reorganization of the cytoskeleton. Application of physiologically relevant forces caused stretching of single talin rods that exposed cryptic binding sites for vinculin. Thus in the talin-vinculin system, molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system. Such protein stretching may be a more general mechanism for force transduction.

1,380 citations

Journal ArticleDOI
25 Nov 2010-Nature
TL;DR: Three-dimensional super-resolution fluorescence microscopy is used to map nanoscale protein organization in focal adhesions and reveals talin’s polarized orientation, indicative of a role in organizing the focal adhesion strata.
Abstract: The physical linkage between the extracellular matrix and the actin cytoskeleton of a cell is made by structures known as focal adhesions, acting through integrin receptors. They are of fundamental importance in human physiology because they mediate cell adhesion, mechanosensing and signalling for the control of cell growth and differentiation. The molecular architecture of focal adhesions has now been determined using three-dimensional super-resolution fluorescence microscopy to map protein organization at the nanoscale level. They are revealed as well-organized ultrastructures in which integrins and actin are separated by a 40-nanometre-long core consisting of partially overlapping protein-specific layers, spanned by talin tethers. The multilaminar architecture creates three or more separate compartments that mediate the interdependent functions of focal adhesions. Focal adhesions link the extracellular matrix by integrin receptors to cytoplasmic actin filaments and are fundamental to human physiology. These authors determine the molecular architecture of focal adhesions by mapping protein organization at the nanoscale level. The results demonstrate that focal adhesions possess a well-organized ultrastructure made up of at least three spatial and functional compartments that mediate their interdependent functions. Cell adhesions to the extracellular matrix (ECM) are necessary for morphogenesis, immunity and wound healing1,2. Focal adhesions are multifunctional organelles that mediate cell–ECM adhesion, force transmission, cytoskeletal regulation and signalling1,2,3. Focal adhesions consist of a complex network4 of trans-plasma-membrane integrins and cytoplasmic proteins that form a <200-nm plaque5,6 linking the ECM to the actin cytoskeleton. The complexity of focal adhesion composition and dynamics implicate an intricate molecular machine7,8. However, focal adhesion molecular architecture remains unknown. Here we used three-dimensional super-resolution fluorescence microscopy (interferometric photoactivated localization microscopy)9 to map nanoscale protein organization in focal adhesions. Our results reveal that integrins and actin are vertically separated by a ∼40-nm focal adhesion core region consisting of multiple protein-specific strata: a membrane-apposed integrin signalling layer containing integrin cytoplasmic tails, focal adhesion kinase and paxillin; an intermediate force-transduction layer containing talin and vinculin; and an uppermost actin-regulatory layer containing zyxin, vasodilator-stimulated phosphoprotein and α-actinin. By localizing amino- and carboxy-terminally tagged talins, we reveal talin’s polarized orientation, indicative of a role in organizing the focal adhesion strata. The composite multilaminar protein architecture provides a molecular blueprint for understanding focal adhesion functions.

1,377 citations

Journal ArticleDOI
01 May 2008-Nature
TL;DR: It is shown here that functional integrins do not contribute to migration in three-dimensional environments, and these cells migrate by the sole force of actin-network expansion, which promotes protrusive flowing of the leading edge.
Abstract: All metazoan cells carry transmembrane receptors of the integrin family, which couple the contractile force of the actomyosin cytoskeleton to the extracellular environment In agreement with this principle, rapidly migrating leukocytes use integrin-mediated adhesion when moving over two-dimensional surfaces As migration on two-dimensional substrates naturally overemphasizes the role of adhesion, the contribution of integrins during three-dimensional movement of leukocytes within tissues has remained controversial We studied the interplay between adhesive, contractile and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro We ablated all integrin heterodimers from murine leukocytes, and show here that functional integrins do not contribute to migration in three-dimensional environments Instead, these cells migrate by the sole force of actin-network expansion, which promotes protrusive flowing of the leading edge Myosin II-dependent contraction is only required on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus

1,288 citations

Journal ArticleDOI
03 Oct 2003-Science
TL;DR: It is reported that specific binding of the cytoskeletal protein talin to integrin β subunit cytoplasmic tails leads to the conformational rearrangements of integrin extracellular domains that increase their affinity.
Abstract: Control of integrin affinity for ligands (integrin activation) is essential for normal cell adhesion, migration, and assembly of an extracellular matrix. Integrin activation is usually mediated through the integrin beta subunit cytoplasmic tail and can be regulated by many different biochemical signaling pathways. We report that specific binding of the cytoskeletal protein talin to integrin beta subunit cytoplasmic tails leads to the conformational rearrangements of integrin extracellular domains that increase their affinity. Thus, regulated binding of talin to integrin beta tails is a final common element of cellular signaling cascades that control integrin activation.

1,212 citations


"Talins and kindlins: partners in in..." refers background in this paper

  • ...RIAM and lamellipodin contain a RAS-associating domain (RA domain) and an adjacent pleckstrin homolog y domain (PH domain), and the structure of the RIAM RA–PH double domain suggests that they act as a proximity detector for activated RAP1A and PtdIns(4,5)P2 (REF....

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  • ...The authors conclude that the major role of PtdInsP kinase Iγ in focal adhesions is to locally synthesize PtdIns(4,5)P2 that is required to orientate the talin head such that it can activate integrins77....

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  • ...A similar phenotype was obtained with wildtype cells expressing a K274E mutation in the talin F2 FERM domain that inhibits PtdIns(4,5)P2binding and dramatically reduces integrin activation37....

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  • ...PtdIns(4,5)P2 has been shown to relieve the F3–R9 interaction62 and could therefore activate talin....

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  • ...76); RIAM and therefore talin are only recruited to RAP1A•GTP embedded in PtdIns(4,5)P2-rich microdomains....

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