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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2014, Vol. 8 Issue (1) : 6-16     DOI: 10.1007/s11684-014-0317-3
Talin and kindlin: the one-two punch in integrin activation
Feng Ye(), Adam K. Snider, Mark H. Ginsberg()
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Proper cell-cell and cell-matrix contacts mediated by integrin adhesion receptors are important for development, immune response, hemostasis and wound healing. Integrins pass trans-membrane signals bidirectionally through their regulated affinities for extracellular ligands and intracellular signaling molecules. Such bidirectional signaling by integrins is enabled by the conformational changes that are often linked among extracellular, transmembrane and cytoplasmic domains. Here, we review how talin-integrin and kindlin-integrin interactions, in cooperation with talin-lipid and kindlin-lipid interactions, regulate integrin affinities and how the progress in these areas helps us understand integrin-related diseases.

Keywords signal transduction      transmembrane domain      nanodisc      integrin      talin      kindling      cell adhesion     
Corresponding Authors: Ye Feng,; Ginsberg Mark H.,   
Issue Date: 26 April 2014
URL:     OR
Fig.1  Structure of integrin αIIbβ3 TMD (ribbon view; αIIb in red and β3 in blue. From PDB 2K9J) showing the two interaction interfaces. Left, outer membrane clasp (OMC). Right, inner membrane clasp (IMC). The important residues for the two interfaces are indicated.
Fig.2  Snorkeling Lys716 fixes the tilting angle of the β3 TMD. On the left, the C of Lys716 resides in the hydrophobic core but its ?-NH group snorkels into the negatively charged phosphate head group region. On the right, when Lys716 is mutated to Glu, the residue shifts away from hydrophobic core to place the side chain -COO group in the aqueous region. This shift causes reduced embedding of β3 TMD and decreased β3 TMD tilting angle.
Fig.3  Talin activates integrin by causing a topology change in β3 TMD. (A) Talin stabilizes the helix in the membrane proximal region of β3 and increases the tilting angle of the continuous β3 TMD. (B) A711P mutation introduces a flexible kink that breaks the continuous β3 TMD, decouples the tilting motion of the two helices, and blocks integrin activation.
Fig.4  Model for talin and kindlin function. Talin promotes affinity increase of individual integrin molecules. Kindlins have little primary effect on affinity of individual integrin but increase multivalent ligand binding by promoting the clustering of talin-activated αIIbβ3.
Fig.5  The dynamic equilibrium of integrin activation functions as signal integrator. The factors that shift the equilibrium to the same direction can add to or synergize with each other. Opposing factors can cancel each other.
1 Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110(6): 673–687
doi: 10.1016/S0092-8674(02)00971-6 pmid:12297042
2 Humphries JD, Byron A, Humphries MJ. Integrin ligands at a glance. J Cell Sci 2006; 119(Pt 19): 3901–3903
doi: 10.1242/jcs.03098 pmid:16988024
3 Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999; 285(5430): 1028–1032
doi: 10.1126/science.285.5430.1028 pmid:10446041
4 Du XP, Plow EF, Frelinger AL3rd, O’Toole TE, Loftus JC, Ginsberg MH. Ligands “activate” integrin alpha IIb beta 3 (platelet GPIIb-IIIa). Cell 1991; 65(3): 409–416
doi: 10.1016/0092-8674(91)90458-B pmid:2018974
5 Zhu J, Carman CV, Kim M, Shimaoka M, Springer TA, Luo BH. Requirement of α and β subunit transmembrane helix separation for integrin outside-in signaling. Blood 2007; 110(7): 2475–2483
doi: 10.1182/blood-2007-03-080077 pmid:17615290
6 Shattil SJ, Newman PJ. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 2004; 104(6): 1606–1615
doi: 10.1182/blood-2004-04-1257 pmid:15205259
7 Kim M, Carman CV, Springer TA. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 2003; 301(5640): 1720–1725
doi: 10.1126/science.1084174 pmid:14500982
8 Bodeau AL, Berrier AL, Mastrangelo AM, Martinez R, LaFlamme SE. A functional comparison of mutations in integrin β cytoplasmic domains: effects on the regulation of tyrosine phosphorylation, cell spreading, cell attachment and β1 integrin conformation. J Cell Sci 2001; 114(Pt 15): 2795–2807
9 Berrier AL, Mastrangelo AM, Downward J, Ginsberg M, LaFlamme SE. Activated R-ras, Rac1, PI 3-kinase and PKCepsilon can each restore cell spreading inhibited by isolated integrin β1 cytoplasmic domains. J Cell Biol 2000; 151(7): 1549–1560
doi: 10.1083/jcb.151.7.1549 pmid:11134082
10 Díaz-González F, Forsyth J, Steiner B, Ginsberg MH. Trans-dominant inhibition of integrin function. Mol Biol Cell 1996; 7(12): 1939–1951
doi: 10.1091/mbc.7.12.1939 pmid:8970156
11 LaFlamme SE, Thomas LA, Yamada SS, Yamada KM. Single subunit chimeric integrins as mimics and inhibitors of endogenous integrin functions in receptor localization, cell spreading and migration, and matrix assembly. J Cell Biol 1994; 126(5): 1287–1298
doi: 10.1083/jcb.126.5.1287 pmid:8063864
12 LaFlamme SE, Akiyama SK, Yamada KM. Regulation of fibronectin receptor distribution. J Cell Biol 1992; 117(2): 437–447
doi: 10.1083/jcb.117.2.437 pmid:1373145
13 Cluzel C, Saltel F, Lussi J, Paulhe F, Imhof BA, Wehrle-Haller B. The mechanisms and dynamics of αvβ3 integrin clustering in living cells. J Cell Biol 2005; 171(2): 383–392
doi: 10.1083/jcb.200503017 pmid:16247034
14 Arias-Salgado EG, Lizano S, Sarkar S, Brugge JS, Ginsberg MH, Shattil SJ. Src kinase activation by direct interaction with the integrin β cytoplasmic domain. Proc Natl Acad Sci USA 2003; 100(23): 13298–13302
doi: 10.1073/pnas.2336149100 pmid:14593208
15 Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol 1995; 131(3): 791–805
doi: 10.1083/jcb.131.3.791 pmid:7593197
16 Miyamoto S, Akiyama SK, Yamada KM. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science 1995; 267(5199): 883–885
doi: 7846531" target="_blank">10.1126/science. pmid:7846531 pmid:7846531
17 Hirahashi J, Mekala D, Van Ziffle J, Xiao L, Saffaripour S, Wagner DD, Shapiro SD, Lowell C, Mayadas TN. Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 2006; 25(2): 271–283
doi: 10.1016/j.immuni.2006.05.014 pmid:16872848
18 Giagulli C, Ottoboni L, Caveggion E, Rossi B, Lowell C, Constantin G, Laudanna C, Berton G. The Src family kinases Hck and Fgr are dispensable for inside-out, chemoattractant-induced signaling regulating β2 integrin affinity and valency in neutrophils, but are required for β2 integrin-mediated outside-in signaling involved in sustained adhesion. J Immunol 2006; 177(1): 604–611
19 Mócsai A, Zhou M, Meng F, Tybulewicz VL, Lowell CA. Syk is required for integrin signaling in neutrophils. Immunity 2002; 16(4): 547–558
doi: 10.1016/S1074-7613(02)00303-5 pmid:11970878
20 McNamee HP, Ingber DE, Schwartz MA. Adhesion to fibronectin stimulates inositol lipid synthesis and enhances PDGF-induced inositol lipid breakdown. J Cell Biol 1993; 121(3): 673–678
doi: 10.1083/jcb.121.3.673 pmid:8387531
21 Schaller MD, Otey CA, Hildebrand JD, Parsons JT. Focal adhesion kinase and paxillin bind to peptides mimicking β integrin cytoplasmic domains. J Cell Biol 1995; 130(5): 1181–1187
doi: 10.1083/jcb.130.5.1181 pmid:7657702
22 Ling K, Doughman RL, Firestone AJ, Bunce MW, Anderson RA. Type I g phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 2002; 420(6911): 89–93
doi: 10.1038/nature01082 pmid:12422220
23 Di Paolo G, Pellegrini L, Letinic K, Cestra G, Zoncu R, Voronov S, Chang S, Guo J, Wenk MR, De Camilli P. Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 g by the FERM domain of talin. Nature 2002; 420(6911): 85–89
doi: 10.1038/nature01147 pmid:12422219
24 Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 2005; 6(1): 56–68
doi: 10.1038/nrm1549 pmid:15688067
25 Choi CK, Vicente-Manzanares M, Zareno J, Whitmore LA, Mogilner A, Horwitz AR. Actin and α-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner. Nat Cell Biol 2008; 10(9): 1039–1050
doi: 10.1038/ncb1763 pmid:19160484
26 Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. Identification of FcgRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets. Blood 2008; 112(7): 2780–2786
doi: 10.1182/blood-2008-02-142125 pmid:18641368
27 Mócsai A, Abram CL, Jakus Z, Hu Y, Lanier LL, Lowell CA. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat Immunol 2006; 7(12): 1326–1333
doi: 10.1038/ni1407 pmid:17086186
28 Abtahian F, Bezman N, Clemens R, Sebzda E, Cheng L, Shattil SJ, Kahn ML, Koretzky GA. Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells. Mol Cell Biol 2006; 26(18): 6936–6949
doi: 10.1128/MCB.01040-06 pmid:16943434
29 del Rio A, Perez-Jimenez R, Liu R, Roca-Cusachs P, Fernandez JM, Sheetz MP. Stretching single talin rod molecules activates vinculin binding. Science 2009; 323(5914): 638–641
doi: 10.1126/science.1162912 pmid:19179532
30 Zhang X, Jiang G, Cai Y, Monkley SJ, Critchley DR, Sheetz MP. Talin depletion reveals independence of initial cell spreading from integrin activation and traction. Nat Cell Biol 2008; 10(9): 1062–1068
doi: 10.1038/ncb1765 pmid:19160486
31 Humphries JD, Wang P, Streuli C, Geiger B, Humphries MJ, Ballestrem C. Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol 2007; 179(5): 1043–1057
doi: 10.1083/jcb.200703036 pmid:18056416
32 Saunders RM, Holt MR, Jennings L, Sutton DH, Barsukov IL, Bobkov A, Liddington RC, Adamson EA, Dunn GA, Critchley DR. Role of vinculin in regulating focal adhesion turnover. Eur J Cell Biol 2006; 85(6): 487–500
doi: 10.1016/j.ejcb.2006.01.014 pmid:16584805
33 Even-Ram S, Artym V, Yamada KM. Matrix control of stem cell fate. Cell 2006; 126(4): 645–647
doi: 10.1016/j.cell.2006.08.008 pmid:16923382
34 Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006; 126(4): 677–689
doi: 10.1016/j.cell.2006.06.044 pmid:16923388
35 Kim C, Ye F, Ginsberg MH. Regulation of integrin activation. Annu Rev Cell Dev Biol 2011; 27(1): 321–345
doi: 10.1146/annurev-cellbio-100109-104104 pmid:21663444
36 Shattil SJ, Kim C, Ginsberg MH. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 2010; 11(4): 288–300
doi: 10.1038/nrm2871 pmid:20308986
37 Wagner CL, Mascelli MA, Neblock DS, Weisman HF, Coller BS, Jordan RE. Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 1996; 88(3): 907–914
38 Shattil SJ, Kashiwagi H, Pampori N. Integrin signaling: the platelet paradigm. Blood 1998; 91(8): 2645–2657
39 Abram CL, Lowell CA. The ins and outs of leukocyte integrin signaling. Annu Rev Immunol 2009; 27(1): 339–362
doi: 10.1146/annurev.immunol.021908.132554 pmid:19302044
40 Pouwels J, Nevo J, Pellinen T, Yl?nne J, Ivaska J. Negative regulators of integrin activity. J Cell Sci 2012; 125(Pt 14): 3271–3280
doi: 10.1242/jcs.093641 pmid:22822081
41 Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007; 25(1): 619–647
doi: 10.1146/annurev.immunol.25.022106.141618 pmid:17201681
42 Arnaout MA, Goodman SL, Xiong JP. Structure and mechanics of integrin-based cell adhesion. Curr Opin Cell Biol 2007; 19(5): 495–507
doi: 10.1016/ pmid:17928215
43 Luo BH, Springer TA. Integrin structures and conformational signaling. Curr Opin Cell Biol 2006; 18(5): 579–586
doi: 10.1016/ pmid:16904883
44 Arnaout MA, Mahalingam B, Xiong JP. Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 2005; 21(1): 381–410
doi: 10.1146/annurev.cellbio.21.090704.151217 pmid:16212500
45 Shimaoka M, Takagi J, Springer TA. Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct 2002; 31(1): 485–516
doi: 10.1146/annurev.biophys.31.101101.140922 pmid:11988479
46 Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell 2008; 32(6): 849–861
doi: 10.1016/j.molcel.2008.11.018 pmid:19111664
47 Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, Arnaout MA. Crystal structure of the extracellular segment of integrin αVβ3. Science 2001; 294(5541): 339–345
doi: 10.1126/science.1064535 pmid:11546839
48 Takagi J, Petre BM, Walz T, Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 2002; 110(5): 599–611
doi: 10.1016/S0092-8674(02)00935-2 pmid:12230977
49 Chen X, Xie C, Nishida N, Li Z, Walz T, Springer TA. Requirement of open headpiece conformation for activation of leukocyte integrin αXβ2. Proc Natl Acad Sci USA 2010; 107(33): 14727–14732
doi: 10.1073/pnas.1008663107 pmid:20679211
50 Luo BH, Strokovich K, Walz T, Springer TA, Takagi J. Allosteric beta1 integrin antibodies that stabilize the low affinity state by preventing the swing-out of the hybrid domain. J Biol Chem 2004; 279(26): 27466–27471
doi: 10.1074/jbc.M404354200 pmid:15123676
51 Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL, Arnaout MA. Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg-Gly-Asp ligand. Science 2002; 296(5565): 151–155
doi: 10.1126/science.1069040 pmid:11884718
52 Adair BD, Xiong JP, Maddock C, Goodman SL, Arnaout MA, Yeager M. Three-dimensional EM structure of the ectodomain of integrin αVβ3 in a complex with fibronectin. J Cell Biol 2005; 168(7): 1109–1118
doi: 10.1083/jcb.200410068 pmid:15795319
53 Ye F, Liu J, Winkler H, Taylor KA. Integrin αIIbβ3 in a membrane environment remains the same height after Mn2+ activation when observed by cryoelectron tomography. J Mol Biol 2008; 378(5): 976–986
doi: 10.1016/j.jmb.2008.03.014 pmid:18405917
54 Mehta RJ, Diefenbach B, Brown A, Cullen E, Jonczyk A, Güssow D, Luckenbach GA, Goodman SL. Transmembrane-truncated αvβ3 integrin retains high affinity for ligand binding: evidence for an “inside-out” suppressor? Biochem J 1998; 330(Pt 2): 861–869
55 Partridge AW, Liu S, Kim S, Bowie JU, Ginsberg MH. Transmembrane domain helix packing stabilizes integrin αIIbβ3 in the low affinity state. J Biol Chem 2005; 280(8): 7294–7300
doi: 10.1074/jbc.M412701200 pmid:15591321
56 Luo BH, Carman CV, Takagi J, Springer TA. Disrupting integrin transmembrane domain heterodimerization increases ligand binding affinity, not valency or clustering. Proc Natl Acad Sci USA 2005; 102(10): 3679–3684
doi: 10.1073/pnas.0409440102 pmid:15738420
57 Li W, Metcalf DG, Gorelik R, Li R, Mitra N, Nanda V, Law PB, Lear JD, Degrado WF, Bennett JS. A push-pull mechanism for regulating integrin function. Proc Natl Acad Sci USA 2005; 102(5): 1424–1429
doi: 10.1073/pnas.0409334102 pmid:15671157
58 Li R, Mitra N, Gratkowski H, Vilaire G, Litvinov R, Nagasami C, Weisel JW, Lear JD, DeGrado WF, Bennett JS. Activation of integrin αIIbβ3 by modulation of transmembrane helix associations. Science 2003; 300(5620): 795–798
doi: 10.1126/science.1079441 pmid:12730600
59 Kim C, Lau TL, Ulmer TS, Ginsberg MH. Interactions of platelet integrin αIIb and β3 transmembrane domains in mammalian cell membranes and their role in integrin activation. Blood 2009; 113(19): 4747–4753
doi: 10.1182/blood-2008-10-186551 pmid:19218549
60 Zhu J, Luo BH, Barth P, Schonbrun J, Baker D, Springer TA. The structure of a receptor with two associating transmembrane domains on the cell surface: integrin αIIbβ3. Mol Cell 2009; 34(2): 234–249
doi: 10.1016/j.molcel.2009.02.022 pmid:19394300
61 Luo BH, Springer TA, Takagi J. A specific interface between integrin transmembrane helices and affinity for ligand. PLoS Biol 2004; 2(6): e153
doi: 10.1371/journal.pbio.0020153 pmid:15208712
62 Lau TL, Kim C, Ginsberg MH, Ulmer TS. The structure of the integrin αIIbβ3 transmembrane complex explains integrin transmembrane signalling. EMBO J 2009; 28(9): 1351–1361
doi: 10.1038/emboj.2009.63 pmid:19279667
63 Li R, Babu CR, Lear JD, Wand AJ, Bennett JS, DeGrado WF. Oligomerization of the integrin αIIbβ3: roles of the transmembrane and cytoplasmic domains. Proc Natl Acad Sci USA 2001; 98(22): 12462–12467
doi: 10.1073/pnas.221463098 pmid:11606749
64 Hughes PE, Diaz-Gonzalez F, Leong L, Wu C, McDonald JA, Shattil SJ, Ginsberg MH. Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J Biol Chem 1996; 271(12): 6571–6574
65 Kim C, Schmidt T, Cho EG, Ye F, Ulmer TS, Ginsberg MH. Basic amino-acid side chains regulate transmembrane integrin signalling. Nature 2012; 481(7380): 209–213
doi: 10.1038/nature10697 pmid:22178926
66 Critchley DR. Biochemical and structural properties of the integrin-associated cytoskeletal protein talin. Annu Rev Biophys 2009; 38(1): 235–254
doi: 10.1146/annurev.biophys.050708.133744 pmid:19416068
67 Elliott PR, Goult BT, Kopp PM, Bate N, Grossmann JG, Roberts GC, Critchley DR, Barsukov IL. The Structure of the talin head reveals a novel extended conformation of the FERM domain. Structure 2010; 18(10): 1289–1299
doi: 10.1016/j.str.2010.07.011 pmid:20947018
68 Calderwood DA, Fujioka Y, de Pereda JM, García-Alvarez B, Nakamoto T, Margolis B, McGlade CJ, Liddington RC, Ginsberg MH. Integrin β cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc Natl Acad Sci USA 2003; 100(5): 2272–2277
doi: 10.1073/pnas.262791999 pmid:12606711
69 Calderwood DA, Yan B, de Pereda JM, Alvarez BG, Fujioka Y, Liddington RC, Ginsberg MH. The phosphotyrosine binding-like domain of talin activates integrins. J Biol Chem 2002; 277(24): 21749–21758
doi: 10.1074/jbc.M111996200 pmid:11932255
70 Lee HS, Lim CJ, Puzon-McLaughlin W, Shattil SJ, Ginsberg MH. RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences. J Biol Chem 2009; 284(8): 5119–5127
doi: 10.1074/jbc.M807117200 pmid:19098287
71 Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B, Calderwood DA, Puzon-McLaughlin W, Lafuente EM, Boussiotis VA, Shattil SJ, Ginsberg MH. Reconstructing and deconstructing agonist-induced activation of integrin αIIbβ3. Curr Biol 2006; 16(18): 1796–1806
doi: 10.1016/j.cub.2006.08.035 pmid:16979556
72 Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH. The Talin head domain binds to integrin β subunit cytoplasmic tails and regulates integrin activation. J Biol Chem 1999; 274(40): 28071–28074
doi: 10.1074/jbc.274.40.28071 pmid:10497155
73 Petrich BG, Marchese P, Ruggeri ZM, Spiess S, Weichert RA, Ye F, Tiedt R, Skoda RC, Monkley SJ, Critchley DR, Ginsberg MH. Talin is required for integrin-mediated platelet function in hemostasis and thrombosis. J Exp Med 2007; 204(13): 3103–3111
doi: 10.1084/jem.20071800 pmid:18086863
74 Nieswandt B, Moser M, Pleines I, Varga-Szabo D, Monkley S, Critchley D, F?ssler R. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J Exp Med 2007; 204(13): 3113–3118
doi: 10.1084/jem.20071827 pmid:18086864
75 Ye F, Hu G, Taylor D, Ratnikov B, Bobkov AA, McLean MA, Sligar SG, Taylor KA, Ginsberg MH. Recreation of the terminal events in physiological integrin activation. J Cell Biol 2010; 188(1): 157–173
doi: 10.1083/jcb.200908045 pmid:20048261
76 Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, Ginsberg MH, Calderwood DA. Talin binding to integrin beta tails: a final common step in integrin activation. Science 2003; 302(5642): 103–106
doi: 10.1126/science.1086652 pmid:14526080
77 Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH, Campbell ID. Structural basis of integrin activation by talin. Cell 2007; 128(1): 171–182
doi: 10.1016/j.cell.2006.10.048 pmid:17218263
78 García-Alvarez B, de Pereda JM, Calderwood DA, Ulmer TS, Critchley D, Campbell ID, Ginsberg MH, Liddington RC. Structural determinants of integrin recognition by talin. Mol Cell 2003; 11(1): 49–58
doi: 10.1016/S1097-2765(02)00823-7 pmid:12535520
79 Tanentzapf G, Brown NH. An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton. Nat Cell Biol 2006; 8(6): 601–606
doi: 10.1038/ncb1411 pmid:16648844
80 Petrich BG, Fogelstrand P, Partridge AW, Yousefi N, Ablooglu AJ, Shattil SJ, Ginsberg MH. The antithrombotic potential of selective blockade of talin-dependent integrin αIIbβ3 (platelet GPIIb-IIIa) activation. J Clin Invest 2007; 117(8): 2250–2259
doi: 10.1172/JCI31024 pmid:17627302
81 Haling JR, Monkley SJ, Critchley DR, Petrich BG. Talin-dependent integrin activation is required for fibrin clot retraction by platelets. Blood 2011; 117(5): 1719–1722
doi: 10.1182/blood-2010-09-305433 pmid:20971947
82 Goult BT, Bouaouina M, Elliott PR, Bate N, Patel B, Gingras AR, Grossmann JG, Roberts GC, Calderwood DA, Critchley DR, Barsukov IL. Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation. EMBO J 2010; 29(6): 1069–1080
doi: 10.1038/emboj.2010.4 pmid:20150896
83 Anthis NJ, Wegener KL, Ye F, Kim C, Goult BT, Lowe ED, Vakonakis I, Bate N, Critchley DR, Ginsberg MH, Campbell ID. The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J 2009; 28(22): 3623–3632
doi: 10.1038/emboj.2009.287 pmid:19798053
84 Kim C, Ye F, Hu X, Ginsberg MH. Talin activates integrins by altering the topology of the β transmembrane domain. J Cell Biol 2012; 197(5): 605–611
doi: 10.1083/jcb.201112141 pmid:22641344
85 Kalli AC, Wegener KL, Goult BT, Anthis NJ, Campbell ID, Sansom MS. The structure of the talin/integrin complex at a lipid bilayer: an NMR and MD simulation study. Structure 2010; 18(10): 1280–1288
doi: 10.1016/j.str.2010.07.012 pmid:20947017
86 Moser M, Legate KR, Zent R, F?ssler R. The tail of integrins, talin, and kindlins. Science 2009; 324(5929): 895–899
doi: 10.1126/science.1163865 pmid:19443776
87 Rogalski TM, Mullen GP, Gilbert MM, Williams BD, Moerman DG. 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 2000; 150(1): 253–264
doi: 10.1083/jcb.150.1.253 pmid:10893272
88 Ussar S, Wang HV, Linder S, F?ssler R, Moser M. The Kindlins: subcellular localization and expression during murine development. Exp Cell Res 2006; 312(16): 3142–3151
doi: 10.1016/j.yexcr.2006.06.030 pmid:16876785
89 Ussar S, Moser M, Widmaier M, Rognoni E, Harrer C, Genzel-Boroviczeny O, F?ssler R. Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genet 2008; 4(12): e1000289
doi: 10.1371/journal.pgen.1000289 pmid:19057668
90 Kloeker S, Major MB, Calderwood DA, Ginsberg MH, Jones DA, Beckerle MC. The Kindler syndrome protein is regulated by transforming growth factor-β and involved in integrin-mediated adhesion. J Biol Chem 2004; 279(8): 6824–6833
doi: 10.1074/jbc.M307978200 pmid:14634021
91 Montanez E, Ussar S, Schifferer M, B?sl M, Zent R, Moser M, F?ssler R. Kindlin-2 controls bidirectional signaling of integrins. Genes Dev 2008; 22(10): 1325–1330
doi: 10.1101/gad.469408 pmid:18483218
92 Harburger DS, Bouaouina M, Calderwood DA. Kindlin-1 and-2 directly bind the C-terminal region of β integrin cytoplasmic tails and exert integrin-specific activation effects. J Biol Chem 2009; 284(17): 11485–11497
doi: 10.1074/jbc.M809233200 pmid:19240021
93 Ma YQ, Qin J, Wu C, Plow EF. Kindlin-2 (Mig-2): a co-activator of β3 integrins. J Cell Biol 2008; 181(3): 439–446
doi: 10.1083/jcb.200710196 pmid:18458155