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  • Review Article
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Talins and kindlins: partners in integrin-mediated adhesion

Nature Reviews Molecular Cell Biology volume 14, pages 503–517 (2013)Cite this article

Subjects

Key Points

  • Integrins are transmembrane receptors that support adhesion to the extracellular matrix and transmit chemical and mechanical signals into and out of cells. Cells regulate integrin-mediated adhesion by controlling integrin affinity for extracellular ligands (integrin activation), by clustering integrins into adhesion complexes (avidity modulation) and by regulating links between integrin cytoplasmic domains and the actin cytoskeleton.

  • The large dimeric actin-binding protein talin is a key regulator of integrin activation, and is composed of an amino-terminal head and a carboxy-terminal flexible rod. The structures of all 18 domains in talin have now been determined, and a model of full-length talin has been generated.

  • Biochemical and structural data reveal how direct interactions between the short cytoplasmic tails of β-integrin subunits and the talin head (a FERM domain) disrupt inhibitory interactions between the integrin α-subunit and β-subunit, inducing conformational changes in the integrin extracellular domains that result in their increased affinity for ligand.

  • The talin rod consists of 13 either 4- or 5-helix bundles, terminating in a single helix that supports talin dimerization. It contains two actin-binding sites and multiple binding sites for the actin-binding protein vinculin, which stabilizes adhesion complexes. Recent data show that the dynamic between talin–RIAM and talin–vinculin interactions is important for integrin activation and force-induced maturation of adhesions.

  • Regulation of talin–integrin interactions represents an important control point along integrin activation pathways. Various regulatory mechanisms have been identified, including talin autoinhibition, competition between talin and other integrin tail-binding or talin-binding proteins and post-translational modification of β-integrin subunits.

  • Although much less well-understood than talins, kindlin family proteins are also known to be important integrin regulators. Kindlin loss, due to knockout, knockdown or disease-causing mutations, result in defective integrin activation.

  • The molecular basis of kindlin function has yet to be determined, but kindlins are structurally related to the talin head, directly bind β-integrin tails and membranes, localize to focal adhesions and synergize with talin during integrin activation.

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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Figure 1: Domain organization and structural model of full-length talin.
Figure 2: Mechanism of talin-mediated integrin activation.
Figure 3: Regulators of talin and kindlin binding to integrins.
Figure 4: Kindlin: an integrin co-activator.
Figure 5: Talin changes partners during adhesion assembly and maturation.

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References

  1. Burridge, K. & Connell, L. A. New protein of adhesion plaques and ruffling membranes. J. Cell Biol. 97, 359–367 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. Critchley, D. R. Biochemical and structural properties of the integrin-associated cytoskeletal protein talin. Annu. Rev. Biophys. 38, 235–254 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Calderwood, D. A. et al. The talin head domain binds to integrin-β subunit cytoplasmic tails and regulates integrin activation. J. Biol. Chem. 274, 28071–28704 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Tadokoro, S. et al. Talin binding to integrin-β tails: a final common step in integrin activation. Science 302, 103–106 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Garcia-Alvarez, B. et al. Structural determinants of integrin recognition by talin. Mol. Cell 11, 49–58 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Wegener, K. L. et al. Structural basis of integrin activation by talin. Cell 128, 171–182 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Calderwood, D. A. Integrin activation. J. Cell Sci. 117, 657–666 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Brown, N. H. et al. Talin is essential for integrin function in Drosophila. Dev. Cell 3, 569–579 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Cram, E. J., Clark, S. G. & Schwarzbauer, J. E. Talin loss-of-function uncovers roles in cell contractility and migration in C. elegans. J. Cell Sci. 116, 3871–3878 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, X. et al. Talin depletion reveals independence of initial cell spreading from integrin activation and traction. Nature Cell Biol. 10, 1062–1068 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Kopp, P. M. et al. Studies on the morphology and spreading of human endothelial cells define key inter- and intramolecular interactions for talin1. Eur. J. Cell Biol. 89, 661–673 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Monkley, S. J. et al. Endothelial cell talin1 is essential for embryonic angiogenesis. Dev. Biol. 349, 494–502 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Moser, M., Nieswandt, B., Ussar, S., Pozgajova, M. & Fassler, R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nature Med. 14, 325–330 (2008). First demonstration that loss of kindlin 3 results in severe defects in platelet integrin activation, revealing the importance of kindlins in integrin activation.

    Article  CAS  PubMed  Google Scholar 

  14. Rogalski, T. M., Mullen, G. P., Gilbert, M. M., Williams, B. D. & Moerman, D. G. The unc-112 gene in Caenorhabditis elegans encodes a novel component of cell–matrix adhesion structures required for integrin localization in the muscle cell membrane. J. Cell Biol. 150, 253–264 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Siegel, D. H. et al. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin–extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am. J. Hum. Genet. 73, 174–187 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jobard, F. et al. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum. Mol. Genet. 12, 925–935 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Karakose, E., Schiller, H. B. & Fassler, R. The kindlins at a glance. J. Cell Sci. 123, 2353–2356 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Kloeker, S. et al. The Kindler syndrome protein is regulated by transforming growth factor-β and involved in integrin-mediated adhesion. J. Biol. Chem. 279, 6824–6833 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Plow, E. F., Qin, J. & Byzova, T. Kindling the flame of integrin activation and function with kindlins. Curr. Opin. Hematol. 16, 323–328 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ye, F., Kim, C. & Ginsberg, M. H. Molecular mechanism of inside–out integrin regulation. J. Thromb. Haemost. 9 (Suppl. 1), 20–25 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anthis, N. J. & Campbell, I. D. The tail of integrin activation. Trends Biochem. Sci. 36, 191–198 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shattil, S. J., Kim, C. & Ginsberg, M. H. The final steps of integrin activation: the end game. Nature Rev. Mol. Cell Biol. 11, 288–300 (2010).

    Article  CAS  Google Scholar 

  23. Peng, X., Nelson, E. S., Maiers, J. L. & DeMali, K. A. New insights into vinculin function and regulation. Int. Rev. Cell. Mol. Biol. 287, 191–231 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ziegler, W. H., Liddington, R. C. & Critchley, D. R. The structure and regulation of vinculin. Trends Cell Biol. 16, 453–460 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Winkler, J., Lunsdorf, H. & Jockusch, B. M. Energy-filtered electron microscopy reveals that talin is a highly flexible protein composed of a series of globular domains. Eur. J. Biochem. 243, 430–436 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Elliott, P. R. et al. The structure of the talin head reveals a novel extended conformation of the FERM domain. Structure 18, 1289–1299 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gingras, A. R. et al. The structure of the C-terminal actin-binding domain of talin. EMBO J. 27, 458–469 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Gingras, A. R. et al. Central region of talin has a unique fold that binds vinculin and actin. J. Biol. Chem. 285, 29577–29587 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gingras, A. R. et al. Structural and dynamic characterization of a vinculin binding site in the talin rod. Biochemistry 45, 1805–1817 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Gingras, A. R. et al. Structural determinants of integrin binding to the talin rod. J. Biol. Chem. 284, 8866–8876 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gingras, A. R. et al. Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod. J. Biol. Chem. 280, 37217–37224 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Goult, B. T. et al. Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation. EMBO J. 29, 1069–1080 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Goult, B. T. et al. The domain structure of talin: residues 1815–1973 form a five-helix bundle containing a cryptic vinculin-binding site. FEBS Lett. 584, 2237–2241 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Papagrigoriou, E. et al. Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle. EMBO J. 23, 2942–2951 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goult, B. T. et al. RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover. J. Biol. Chem. 288, 8238–8249 (2013). Presents a structural model for full-length talin and provides a structural basis for a switch from talin–RIAM to talin–vinculin complexes during adhesion assembly and maturation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Anthis, N. J., Wegener, K. L., Critchley, D. R. & Campbell, I. D. Structural diversity in integrin/talin interactions. Structure 18, 1654–1666 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Anthis, N. J. et al. The structure of an integrin/talin complex reveals the basis of inside–out signal transduction. EMBO J. 28, 3623–3632 (2009). The first structure of a full-length β-integrin tail bound to the talin F2–F3 FERM domains. This, combined with biophysical studies and integrin activation assays, reveals that talin F3 binding to the membrane-proximal helix of the β-integrin tail disrupts an inhibitory α-integrin tail–β-integrin tail interaction, and identifies an important positively charged membrane-binding surface on the talin F2 domain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wegener, K. L. et al. Structural basis for the interaction between the cytoplasmic domain of the hyaluronate receptor layilin and the talin F3 subdomain. J. Mol. Biol. 382, 112–126 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. de Pereda, J. M. et al. Structural basis for phosphatidylinositol phosphate kinase type Iγ binding to talin at focal adhesions. J. Biol. Chem. 280, 8381–8386 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Lawson, C. et al. FAK promotes recruitment of talin to nascent adhesions to control cell motility. J. Cell Biol. 196, 223–232 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang, S. et al. Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration. J. Cell Biol. 199, 331–345 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bate, N. et al. Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics. PLoS ONE 7, e34461 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rodius, S. et al. The talin rod IBS2 α-helix interacts with the β3 integrin cytoplasmic tail membrane-proximal helix by establishing charge complementary salt bridges. J. Biol. Chem. 283, 24212–24223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Han, J. et al. Reconstructing and deconstructing agonist-induced activation of integrin αIIbβ3. Curr. Biol. 16, 1796–1806 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Lee, H. S., Lim, C. J., Puzon-McLaughlin, W., Shattil, S. J. & Ginsberg, M. H. RIAM activates integrins by linking talin to Ras GTPase membrane-targeting sequences. J. Biol. Chem. 284, 5119–5127 (2009). Provides the first insights into how the RAP1A effector RIAM binds to talin and recruits it to the membrane to activate integrins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Watanabe, N. et al. Mechanisms and consequences of agonist-induced talin recruitment to platelet integrin αIIbβ3. J. Cell Biol. 181, 1211–1222 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, G. et al. Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK). Proc. Natl Acad. Sci. USA 108, 17129–17134 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sun, N., Critchley, D. R., Paulin, D., Li, Z. & Robson, R. M. Identification of a repeated domain within mammalian α-synemin that interacts directly with talin. Exp. Cell Res. 314, 1839–1849 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Petrich, B. G. Talin-dependent integrin signalling in vivo. Thromb. Haemost. 101, 1020–1024 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Lau, T. L., Kim, C., Ginsberg, M. H. & Ulmer, T. S. The structure of the integrin αIIbβ3 transmembrane complex explains integrin transmembrane signalling. EMBO J. 28, 1351–1361 (2009). An NMR structure that provides key information about the complex formed by the membrane-spanning helices in the inactive integrin state.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhu, J. et al. The structure of a receptor with two associating transmembrane domains on the cell surface: integrin αIIbβ3. Mol. Cell 34, 234–249 (2009). A structure of the membrane-spanning region of an intact integrin, determined by disulfide crosslinking and molecular modelling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kim, C. et al. Basic amino-acid side chains regulate transmembrane integrin signalling. Nature 481, 209–213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kalli, A. C., Campbell, I. D. & Sansom, M. S. P. Multiscale simulations suggest a mechanism for integrin inside–out activation. Proc. Natl Acad. Sci. USA 108, 11890–11895 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kim, C., Ye, F., Hu, X. & Ginsberg, M. H. Talin activates integrins by altering the topology of the β-transmembrane domain. J. Cell Biol. 197, 605–611 (2012). Demonstrates, together with reference 52, using environment-sensitive fluorophores, that talin binding to the β-integrin TMD alters the membrane embedding of this region.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Moore, D. T. et al. Affinity of talin-1 for the β3-integrin cytosolic domain is modulated by its phospholipid bilayer environment. Proc. Natl Acad. Sci. USA 109, 793–798 (2012).

    Article  PubMed  Google Scholar 

  56. Lefort, C. T. et al. Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood 119, 4275–4282 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nieswandt, B. et al. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J. Exp. Med. 204, 3113–3118 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Petrich, B. G. et al. Talin is required for integrin-mediated platelet function in hemostasis and thrombosis. J. Exp. Med. 204, 3103–3111 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Haling, J. R., Monkley, S. J., Critchley, D. R. & Petrich, B. G. Talin-dependent integrin activation is required for fibrin clot retraction by platelets. Blood 117, 1719–1722 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim, M., Carman, C. V. & Springer, T. A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301, 1720–1725 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Bouaouina, M., Harburger, D. S. & Calderwood, D. A. Talin and signaling through integrins. Methods Mol. Biol. 757, 325–347 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Goksoy, E. et al. Structural basis for the autoinhibition of talin in regulating integrin activation. Mol. Cell 31, 124–133 (2008). The first biochemical and structural data showing how binding of the talin head to the rod occludes the integrin-binding site in the head and how talin autoinhibition might be relieved by PtdIns(4,5)P 2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Goult, B. et al. Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation. J. Struct. Biol. http://dx.doi.org/10.1016/j.jsb.2013.05.014 (2013).

  64. Goult, B. T. et al. The structure of an interdomain complex that regulates talin activity. J. Biol. Chem. 284, 15097–15106 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Song, X. et al. A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion. Cell Res. 22, 1533–1545 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Saltel, F. et al. New PI(4,5)P2 and membrane proximal integrin-binding motifs in the talin head control β3-integrin clustering. J. Cell Biol. 187, 715–731 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Helsten, T. L. et al. Differences in regulation of Drosophila and vertebrate integrin affinity by talin. Mol. Biol. Cell 19, 3589–3598 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bunch, T. A. Integrin αIIbβ3 activation in Chinese hamster ovary cells and platelets increases clustering rather than affinity. J. Biol. Chem. 285, 1841–1849 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Molony, L., Mccaslin, D., Abernethy, J., Paschal, B. & Burridge, K. Properties of talin from chicken gizzard smooth-muscle. J. Biol. Chem. 262, 7790–7795 (1987).

    CAS  PubMed  Google Scholar 

  70. Banno, A. et al. Subcellular localization of talin is regulated by inter-domain interactions. J. Biol. Chem. 287, 13799–13812 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bakolitsa, C. et al. Structural basis for vinculin activation at sites of cell adhesion. Nature 430, 583–586 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Humphries, J. D. et al. Vinculin controls focal adhesion formation by direct interactions with talin and actin. J. Cell Biol. 179, 1043–1057 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Carisey, A. et al. Vinculin regulates the recruitment and release of core focal adhesion proteins in a force-dependent manner. Curr. Biol. 23, 271–281 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee, H. S., Anekal, P., Lim, C. J., Liu, C. C. & Ginsberg, M. H. Two modes of integrin activation form a binary molecular switch in adhesion maturation. Mol. Biol. Cell 24, 1354–1362 (2013). Provides evidence that vinculin displaces RIAM from talin, and that this drives the transition from dynamic RIAM-positive nascent adhesions that support membrane protrusion to more stable vinculin-rich force-bearing focal adhesions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Colo, G. P., Lafuente, E. M. & Teixido, J. The MRL proteins: adapting cell adhesion, migration and growth. Eur. J. Cell Biol. 91, 861–868 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Wynne, J. P. et al. Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector. J. Cell Biol. 199, 317–329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Legate, K. R. et al. Integrin adhesion and force coupling are independently regulated by localized PtdIns(4,5)2 synthesis. EMBO J. 30, 4539–4553 (2011). Provides definitive evidence that PtdIns(4,5)P 2 generated by the talin-binding isoform of PtdInsP kinase Iγ in focal adhesions is essential for the formation of initial integrin-mediated cell attachment and for the subsequent linkage of integrins to cytoskeletal actin and the exertion of force on the matrix.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Thapa, N. et al. Phosphoinositide signaling regulates the exocyst complex and polarized integrin trafficking in directionally migrating cells. Dev. Cell 22, 116–130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Li, X. et al. Ubiquitination of PIPKIγ90 by HECTD1 regulates focal adhesion dynamics and cell migration. J. Cell Sci. 126, 2617–2628 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Miller, N. L., Lawson, C., Chen, X. L., Lim, S. T. & Schlaepfer, D. D. Rgnef (p190RhoGEF) knockout inhibits RhoA activity, focal adhesion establishment, and cell motility downstream of integrins. PLoS ONE 7, e37830 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rossier, O. et al. Integrins β1 and β3 exhibit distinct dynamic nanoscale organizations inside focal adhesions. Nature Cell Biol. 14, 1057–1067 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Wang, P., Ballestrem, C. & Streuli, C. H. The C-terminus of talin links integrins to cell cycle progression. J. Cell Biol. 195, 499–513 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pouwels, J., Nevo, J., Pellinen, T., Ylanne, J. & Ivaska, J. Negative regulators of integrin activity. J. Cell Sci. 125, 3271–3280 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Anthis, N. J. et al. β-integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation. J. Biol. Chem. 284, 36700–36710 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Oxley, C. L. et al. An integrin phosphorylation switch: the effect of β3 integrin tail phosphorylation on Dok1 and talin binding. J. Biol. Chem. 283, 5420–5426 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Calderwood, D. A. et al. Integrin-β cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc. Natl Acad. Sci. USA 100, 2272–2277 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kiema, T. et al. The molecular basis of filamin binding to integrins and competition with talin. Mol. Cell 21, 337–347 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Ithychanda, S. S. et al. Migfilin, a molecular switch in regulation of integrin activation. J. Biol. Chem. 284, 4713–4722 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lad, Y. et al. Structural basis of the migfilin–filamin interaction and competition with integrin-β tails. J. Biol. Chem. 283, 35154–35163 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Das, M., Ithychanda, S. S., Qin, J. & Plow, E. F. Migfilin and filamin as regulators of integrin activation in endothelial cells and neutrophils. PLoS ONE 6, e26355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Moik, D. V., Janbandhu, V. C. & Fassler, R. Loss of migfilin expression has no overt consequences on murine development and homeostasis. J. Cell Sci. 124, 414–421 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Xiao, G. et al. Critical role of filamin-binding LIM protein 1 (FBLP-1)/migfilin in regulation of bone remodeling. J. Biol. Chem. 287, 21450–21460 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Takala, H. et al. β2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding. Blood 112, 1853–1862 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Millon-Fremillon, A. et al. Cell adaptive response to extracellular matrix density is controlled by ICAP-1-dependent β1-integrin affinity. J. Cell Biol. 180, 427–441 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu, W., Draheim, K. M., Zhang, R., Calderwood, D. A. & Boggon, T. J. Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation. Mol. Cell 49, 719–729 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Roca-Cusachs, P. et al. Integrin-dependent force transmission to the extracellular matrix by α-actinin triggers adhesion maturation. Proc. Natl Acad. Sci. USA 110, e1361–e1370 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Tadokoro, S. et al. A potential role for α-actinin in inside–out αIIbβ3 signaling. Blood 117, 250–258 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Calderwood, D. A., Tai, V., Di Paolo, G., De Camilli, P. & Ginsberg, M. H. Competition for talin results in trans-dominant inhibition of integrin activation. J. Biol. Chem. 279, 28889–28895 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Bouaouina, M. & Calderwood, D. A. Kindlins. Curr. Biol. 21, R99–R101 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Ye, F. & Petrich, B. G. Kindlin: helper, co-activator, or booster of talin in integrin activation? Curr. Opin. Hematol. 18, 356–360 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Harburger, D. S., Bouaouina, M. & Calderwood, D. A. Kindlin-1 and -2 directly bind the C-terminal region of β-integrin cytoplasmic tails and exert integrin-specific activation effects. J. Biol. Chem. 284, 11485–11497 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ma, Y. Q., Qin, J., Wu, C. & Plow, E. F. Kindlin-2 (Mig-2): a co-activator of β3 integrins. J. Cell Biol. 181, 439–446 (2008). Provides evidence for the cooperativity between the talin head and kindlin 2 in integrin activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Montanez, E. et al. Kindlin-2 controls bidirectional signaling of integrins. Genes Dev. 22, 1325–1330 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Malinin, N. L. et al. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nature Med. 15, 313–318 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Qu, H. et al. Kindlin-2 regulates podocyte adhesion and fibronectin matrix deposition through interactions with phosphoinositides and integrins. J. Cell Sci. 124, 879–891 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bledzka, K. et al. Spatial coordination of kindlin-2 with talin head domain in interaction with integrin-β cytoplasmic tails. J. Biol. Chem. 287, 24585–24594 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ye, F. et al. Recreation of the terminal events in physiological integrin activation. J. Cell Biol. 188, 157–173 (2010). Establishes that purified talin components, in an in vitro nanodisc system, are sufficient to activate isolated membrane-embedded integrins, even in the absence of kindlin. Also provides support for a model whereby integrins adopt a more upright orientation when activated.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Goult, B. T. et al. The structure of the N-terminus of kindlin-1: a domain important for αIIbβ3 integrin activation. J. Mol. Biol. 394, 944–956 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Perera, H. D. et al. Membrane binding of the N-terminal ubiquitin-like domain of kindlin-2 is crucial for its regulation of integrin activation. Structure 19, 1664–1671 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Liu, J. et al. Structural basis of phosphoinositide binding to kindlin-2 protein pleckstrin homology domain in regulating integrin activation. J. Biol. Chem. 286, 43334–43342 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Liu, Y., Zhu, Y., Ye, S. & Zhang, R. Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation. Protein Cell 3, 434–440 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yates, L. A. et al. Structural and functional characterisation of the kindlin-1 pleckstrin homology domain. J. Biol. Chem. 287, 43246–43261 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Yates, L. A., Fuzery, A. K., Bonet, R., Campbell, I. D. & Gilbert, R. J. C. Biophysical analysis of kindlin-3 reveals an elongated conformation and maps integrin binding to the membrane-distal β-subunit, NPXY motif. J. Biol. Chem. 287, 37715–37731 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Moser, M., Legate, K. R., Zent, R. & Fassler, R. The tail of integrins, talin, and kindlins. Science 324, 895–899 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Kahner, B. N. et al. Kindlins, integrin activation and the regulation of talin recruitment to αIIbβ3. PLoS ONE 7, e34056 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bouaouina, M. et al. A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation. J. Biol. Chem. 287, 6979–6990 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Honda, S. et al. Integrin-linked kinase associated with integrin activation. Blood 113, 5304–5313 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Bandyopadhyay, A., Rothschild, G., Kim, S., Calderwood, D. A. & Raghavan, S. Functional differences between kindlin-1 and kindlin-2 in keratinocytes. J. Cell Sci. 125, 2172–2184 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bialkowska, K. et al. The integrin co-activator Kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell. J. Biol. Chem. 285, 18640–18649 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ussar, S. et al. Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genet. 4, e1000289 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Roca-Cusachs, P., Gauthier, N. C., Del Rio, A. & Sheetz, M. P. Clustering of α5β1 integrins determines adhesion strength whereas αvβ3 and talin enable mechanotransduction. Proc. Natl Acad. Sci. USA 106, 16245–16250 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. del Rio, A. et al. Stretching single talin rod molecules activates vinculin binding. Science 323, 638–641 (2009). Use of magnetic tweezers, total internal reflection fluorescence and atomic force microscopy showed that physiologically relevant forces cause stretching of talin and result in exposure of cryptic VBSs.

    Article  CAS  PubMed  Google Scholar 

  123. Pasapera, A. M., Schneider, I. C., Rericha, E., Schlaepfer, D. D. & Waterman, C. M. Myosin II activity regulates vinculin recruitment to focal adhesions through FAK-mediated paxillin phosphorylation. J. Cell Biol. 188, 877–890 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Margadant, F. et al. Mechanotransduction in vivo by repeated talin stretch-relaxation events depends upon vinculin. PLoS Biol. 9, e1001223 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Smith, S. J. & McCann, R. O. A. C-terminal dimerization motif is required for focal adhesion targeting of talin1 and the interaction of the talin1 I/LWEQ module with F-actin. Biochemistry 46, 10886–10898 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Ellis, S. J., Pines, M., Fairchild, M. J. & Tanentzapf, G. In vivo functional analysis reveals specific roles for the integrin-binding sites of talin. J. Cell Sci. 124, 1844–1856 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Parsons, M., Messent, A. J., Humphries, J. D., Deakin, N. O. & Humphries, M. J. Quantification of integrin receptor agonism by fluorescence lifetime imaging. J. Cell Sci. 121, 265–271 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Kanchanawong, P. et al. Nanoscale architecture of integrin-based cell adhesions. Nature 468, 580–584 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang, F., Saha, S. & Kashina, A. Arginylation-dependent regulation of a proteolytic product of talin is essential for cell–cell adhesion. J. Cell Biol. 197, 819–836 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Debrand, E. et al. Talin 2 is a large and complex gene encoding multiple transcripts and protein isoforms. FEBS J. 276, 1610–1628 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Franco, S. J. et al. Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nature Cell Biol. 6, 977–983 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Huang, C. et al. Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration. Nature Cell Biol. 11, 624–630 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Bridgewater, R. E., Norman, J. C. & Caswell, P. T. Integrin trafficking at a glance. J. Cell Sci. 125, 3695–3701 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Albiges-Rizo, C., Frachet, P. & Block, M. R. Down regulation of talin alters cell adhesion and the processing of the a5b1 integrin. J. Cell Sci. 108, 3317–3329 (1995).

    CAS  PubMed  Google Scholar 

  135. Martel, V. et al. Talin controls the exit of the integrin a5b1 from an early compartment of the secretory pathway. J. Cell Sci. 113, 1951–1961 (2000).

    CAS  PubMed  Google Scholar 

  136. Priddle, H. et al. Disruption of the talin gene compromises focal adhesion assembly in undifferentiated but not differentiated ES cells. J. Cell Biol. 142, 1121–1133 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Liu, J. et al. Talin1 regulates integrin turnover to promote embryonic epithelial morphogenesis. Mol. Cell. Biol. 31, 3366–3377 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Margadant, C., Kreft, M., de Groot, D. J., Norman, J. C. & Sonnenberg, A. Distinct roles of talin and kindlin in regulating integrin α5β1 function and trafficking. Curr. Biol. 22, 1554–1563 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Bottcher, R. T. et al. Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β1-integrin tail. Nature Cell Biol. 14, 584–592 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Steinberg, F., Heesom, K. J., Bass, M. D. & Cullen, P. J. SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. J. Cell Biol. 197, 219–230 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Choi, C. K., Zareno, J., Digman, M. A., Gratton, E. & Horwitz, A. R. Cross-correlated fluctuation analysis reveals phosphorylation-regulated paxillin–FAK complexes in nascent adhesions. Biophys. J. 100, 583–592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhao, Y. et al. Regulation of cell adhesion and migration by Kindlin-3 cleavage by calpain. J. Biol. Chem. 287, 40012–40020 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bledzka, K. et al. Tyrosine phosphorylation of integrin β3 regulates kindlin-2 binding and integrin activation. J. Biol. Chem. 285, 30370–30374 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Qadota, H., Moerman, D. G. & Benian, G. M. A molecular mechanism for the requirement of PAT-4 (integrin-linked kinase (ILK)) for the localization of UNC-112 (Kindlin) to integrin adhesion sites. J. Biol. Chem. 287, 28537–28551 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Debrand, E. et al. Mice carrying a complete deletion of the talin2 coding sequence are viable and fertile. Biochem. Biophys. Res. Commun. 426, 190–195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Desiniotis, A. & Kyprianou, N. Significance of talin in cancer progression and metastasis. Int. Rev. Cell Mol. Biol. 289, 117–147 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kato, H. et al. The primacy of β1 integrin activation in the metastatic cascade. PLoS ONE 7, e46576 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

    Article  CAS  PubMed  Google Scholar 

  149. Dong, X. et al. αVβ3 integrin crystal structures and their functional implications. Biochemistry 51, 8814–8828 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Bouaouina, M. et al. Zasp regulates integrin activation. J. Cell Sci. 125, 5647–5657 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Monkley, S. J. et al. Disruption of the talin gene arrests mouse development at the gastrulation stage. Dev. Dyn. 219, 560–574 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Wang, Y. et al. Loss of PIP5KIγ, unlike other PIP5KI isoforms, impairs the integrity of the membrane cytoskeleton in murine megakaryocytes. J. Clin. Invest. 118, 812–819 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Wernimont, S. A. et al. Contact-dependent T cell activation and T cell stopping require Talin1. J. Immunol. 187, 6256–6267 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Manevich-Mendelson, E. et al. Talin1 is required for integrin-dependent B lymphocyte homing to lymph nodes and the bone marrow but not for follicular B-cell maturation in the spleen. Blood 116, 5907–5918 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Lammermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. Conti, F. J. et al. Progressive myopathy and defects in the maintenance of myotendinous junctions in mice that lack talin 1 in skeletal muscle. Development 135, 2043–2053 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Zou, W. et al. Talin1 and Rap1 are critical for osteoclast function. Mol. Cell. Biol. 33, 830–844 (2012).

    Article  CAS  PubMed  Google Scholar 

  158. Manso, A. et al. Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload. J. Biol. Chem. 288, 4252–4264 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Conti, F. J., Monkley, S. J., Wood, M. R., Critchley, D. R. & Muller, U. Talin 1 and 2 are required for myoblast fusion, sarcomere assembly and the maintenance of myotendinous junctions. Development 136, 3597–3606 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bouvard, D., Pouwels, J., De Franceschi, N. & Ivaska, J. Integrin inactivators: balancing cellular fiunctions in vitro and in vivo. Nature Rev. Mol. Cell Biol. 14, 432–444 (2013).

    Article  CAS  Google Scholar 

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Acknowledgements

Work in the authors laboratories was supported by the National Institutes of Health (NIH), the Medical Research Council, the Wellcome Trust, Cancer Research UK and the Medical Research Council. They thank members of the Calderwood laboratory for their input during preparation of the mansucript, B. Goult for help in preparing figure 1 and A. Kalli for contributions to figure 2c. They apologize to colleagues whose work could not be cited or fully discussed due to space limitations.

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Authors and Affiliations

  1. Departments of Pharmacology and of Cell Biology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    David A. Calderwood

  2. Department of Biochemistry, University of Oxford, S. Parks Road, Oxford, OX1 3QU, UK

    Iain D. Campbell

  3. Department of Biochemistry, University of Leicester, Leicester, LE1 7RH

    David R. Critchley

Authors
  1. David A. Calderwood
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  2. Iain D. Campbell
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  3. David R. Critchley
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Correspondence to David A. Calderwood, Iain D. Campbell or David R. Critchley.

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Glossary

FERM domain

Found in various cytoskeletal-associated proteins, including band 4.1, ezrin, radixin and moesin, the proteins after which this domain was named. One role of this domain is to localize proteins to the plasma membrane. It typically contains three subdomains, F1, F2 and F3, that normally arranged in a cloverleaf formation.

Nanodiscs

A synthetic model membrane system made from lipids and a scaffold protein. They are used to study incorporated membrane proteins, such as integrins, because they are relatively small, monodisperse and homogenous, yet provide a native-like environment.

Leukocyte adhesion deficiency type III

(LADIII). A rare genetic disease characterized by severe bacterial infections and bleeding disorders. It is caused by mutations in the gene encoding kindlin 3 in haematopoietic cells.

Multiscale molecular dynamics simulations

These numerically solve Newton's equations for interacting particles and follow their trajectories. They have become a powerful way of fine-tuning protein structure and dynamics. Major limitations are the relatively small size of the systems and the short timescales of the trajectories that can be studied. Multiscale simulations that combine simplified representations of molecules (coarse grain) with all atom representations (atomistic) circumvent some limitations.

SAXS

(Small angle X-ray scattering). A technique that provides low-resolution information about the shape of objects. It depends on the analysis of the angular intensity distribution of X-rays scattered by molecules in solution.

RAS-associating domain

(RA domain). A domain that is found in many effector proteins for the RAS family of small GTPases. The domain adopts a ubiquitin-like fold and supports binding of proteins containing an RA domain to 'active' GTP-loaded RAS family proteins.

Pleckstrin homology domain

(PH domain). Domain that is found in a wide range of intracellular signalling proteins. It often binds to membranes via interactions with phosphatidylinositol-4,5-bisphosphate.

Exocyst complex

An octameric protein complex that is involved in vesicle trafficking. It targets post-Golgi vesicles to the plasma membrane before vesicle fusion.

PTB domain

(Phosphotyrosine-binding domain). Domain found in a wide range of intracellular signalling proteins. It commonly binds NPXY motifs; the Y may require phosphorylation to support binding.

KRIT1

(Krev interaction trapped 1). This protein, which is encoded by the CCM1 gene, is a multidomain adaptor that is important for cell–cell and cell–matrix adhesion. Loss-of-function mutations in CCM1 cause predisposition to cerebral cavernous malformations, which are neurovascular anomalies that increase the risk of haemorrhagic stroke.

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Calderwood, D., Campbell, I. & Critchley, D. Talins and kindlins: partners in integrin-mediated adhesion. Nat Rev Mol Cell Biol 14, 503–517 (2013). https://doi.org/10.1038/nrm3624

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