Kindling the flame of integrin activation and function with kindlins

Current Opinion in Hematology

Volumn 16, Issue 5, 2009, Pages 323-328

  Plow, Edward F ^a   Qin, Jun ^a   Byzova, Tatiana ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

Author keywords

Integrins; Kindlin 1; Kindlin 2; Kindlin 3; Talin

Indexed keywords

EZRIN; INTEGRIN; MEMBRANE PROTEIN; MOESIN; PROTEIN KINDLIN 1; PROTEIN KINDLIN 2; PROTEIN KINDLIN 3; RADIXIN; TALIN; UNCLASSIFIED DRUG;

ALBERS SCHOENBERG DISEASE; BLEEDING; CAENORHABDITIS ELEGANS; CELLULAR DISTRIBUTION; EMBRYO DEATH; ENTEROPATHY; ERYTHROCYTE FUNCTION AND CHARACTERISTICS; GENE MUTATION; HEART DISEASE; HUMAN; INFECTION; KINDLING; LEUKOCYTE FUNCTION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; SKIN DEFECT; THROMBOCYTE DYSFUNCTION; TISSUE DISTRIBUTION;

ANIMALS; CYTOSKELETAL PROTEINS; HUMANS; INTEGRINS; MEMBRANE PROTEINS; NEOPLASM PROTEINS;

EID: 69549114537     PISSN: 10656251     EISSN: 15317048     Source Type: Journal    
DOI: 10.1097/MOH.0b013e32832ea389     Document Type: Review

References (67)

1. Kindler T. Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy. Br J Dermatol 1954; 66:104-111.
2. Ashton GH. Kindler syndrome. Clin Exp Dermatol 2004; 29:116-121.
3. Arita K, Wessagowit V, Inamadar AC, et al. Unusual molecular findings in Kindler syndrome. Br J Dermatol 2007; 157:1252-1256. (Pubitemid 350115668)
4. Rogalski TM, Mullen GP, Gilbert MM, et al. 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; 150:253-264.
5. Larjava H, Plow EF, Wu C. Kindlins: essential regulators of integrin signalling and cell-matrix adhesion. EMBO Rep 2008; 9:1203-1208. This article provides a comprehensive review of kindlins, their structure and function.
6. Ussar S, Wang HV, Linder S, et al. The kindlins: subcellular localization and expression during murine development. Exp Cell Res 2006; 312:3142-3151. (Pubitemid 44292664)
7. Gozgit JM, Pentecost BT, Marconi SA, et al. Use of an aggressive MCF-7 cell line variant, TMX2-28, to study cell invasion in breast cancer. Mol Cancer Res 2006; 4:905-913.
8. Kato K, Shiozawa T, Mitsushita J, et al. Expression of the mitogen-inducible gene-2 (mig-2) is elevated in human uterine leiomyomas but not in leiomyosarcomas. Hum Pathol 2004; 35:55-60. (Pubitemid 38133923)
9. Weinstein EJ, Bourner M, Head R, et al. URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is signifi- cantly over-expressed in lung and colon carcinomas. Biochim Biophys Acta 2003; 1637:207-216. (Pubitemid 36407771)
10. Mackinnon AC, Qadota H, Norman KR, et al. C. elegans PAT-4/ILK functions as an adaptor protein within integrin adhesion complexes. Curr Biol 2002; 12:787-797. (Pubitemid 34514364)
11. Chishti AH, Kim AC, Marfatia SM, et al. The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends Biochem Sci 1998; 23:281-282.
12. Kloeker S, Major MB, Calderwood DA, et al. The Kindler syndrome protein is regulated by transforming growth factor-beta and involved in integrinmediated adhesion. J Biol Chem 2004; 279:6824-6833. (Pubitemid 38248824)
13. Calderwood DA, Yan B, de Pereda JM, et al. The phosphotyrosine binding (PTB)-like domain of talin activates integrins. J Biol Chem 2002; 277:21749-21758. (Pubitemid 34952326)
14. Tu Y, Wu S, Shi X, et al. Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell 2003; 113:37-47. (Pubitemid 36411958)
15. Shi X, Wu C. A suppressive role of mitogen inducible gene-2 in mesenchymal cancer cell invasion. Mol Cancer Res 2008; 6:715-724. This study demonstrates that kindlin-2 (mig-2) influences the invasive properties of mesenchymal cancer cells.
16. Moser M, Nieswandt B, Ussar S, et al. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 2008; 14:325-330. This study describes the hemostatic defects in kindlin-3-deficient mice, showing that platelet aggregation in response to all agonists is absent and thrombus formation is blunted. The hemostatic defect is assigned to an absence of kindlin-3 binding to the cytoplasmic tail of the integrin β3 subunit. (Pubitemid 351347914)
17. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110:673-687.
18. Ginsberg MH, Partridge A, Shattil SJ. Integrin regulation. Curr Opin Cell Biol 2005; 17:509-516.
19. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signalling. Annu Rev Immunol 2007; 25:619-647. (Pubitemid 46697919)
20. Shattil SJ, Newman PJ. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 2004; 104:1606-1615. (Pubitemid 39202265)
21. Ma YQ, Qin J, Plow EF. Platelet integrin aIIbβ3: activation mechanisms. J Thromb Haemost 2007; 5:1345-1352.
22. Arnaout MA. Integrin structure: new twists and turns in dynamic cell adhesion. Immunol Rev 2002; 186:125-146.
23. Xiao T, Takagi J, Coller BS, et al. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 2004; 432:59-67. (Pubitemid 39490825)
24. Zhu J, Luo BH, Xiao T, et al. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell 2008; 32:849-861. This study provides the crystal structure of the ECD of integrin aIIbβ3 and shows the transitions that occur during activation of the integrin.
25. Vinogradova O, Velyvis A, Velyviene A, et al. A structural mechanism of integrin aIIbβ3 'inside-out' activation as regulated by its cytoplasmic face. Cell 2002; 110:587-597.
26. Ulmer TS, Yaspan B, Ginsberg MH, Campbell ID. NMR analysis of structure and dynamics of the cytosolic tails of integrin alphaIIbbeta3 in aqueous solution. Biochemistry 2001; 40:7498-7508. (Pubitemid 32578014)
27. Weljie AM, Hwang PM, Vogel HJ. Solution structures of the cytoplasmic tail complex from platelet integrin alpha IIb- and beta 3-subunits. Proc Natl Acad Sci USA 2002; 99:5878-5883.
28. Hughes PE, Diaz-Gonzalez F, Leong L, et al. Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J Biol Chem 1996; 271:6571-6574. (Pubitemid 26104079)
29. Ma YQ, Yang J, Pesho MM, et al. Regulation of Integrin alpha(IIb)beta(3) activation by distinct regions of its cytoplasmic tails. Biochemistry 2006; 45:6656-6662.
30. Ghevaert C, Salsmann A, Watkins NA, et al. A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia. Blood 2008; 111:3407-3414.
31. Imai Y, Park EJ, Peer D, et al. Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates {alpha}4 integrins. Blood 2008; 112:5007-5015.
32. Czuchra A, Meyer H, Legate KR, et al. Genetic analysis of beta1 integrin 'activation motifs' in mice. J Cell Biol 2006; 174:889-899.
33. Lau TL, Dua V, Ulmer TS. Structure of the integrin alphaIIb transmembrane segment. J Biol Chem 2008; 283:16162-16168.
34. Lau TL, Partridge AW, Ginsberg MH, Ulmer TS. Structure of the integrin beta3 transmembrane segment in phospholipid bicelles and detergent micelles. Biochemistry 2008; 47:4008-4016.
35. 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 U S A 2005; 102:3679-3684. (Pubitemid 40354671)
36. Kim C, Lau TL, Ulmer TS, Ginsberg MH. Interactions of platelet integrin {alpha}IIb and {beta}3 transmembrane domains in mammalian cell membranes and their role in integrin activation. Blood 2009; 113:1347-1353.
37. Calderwood DA, Zent R, Grant R, et al. The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J Biol Chem 1999; 274:28071-28074. (Pubitemid 129504663)
38. Tadokoro S, Shattil SJ, Eto K, et al. Talin binding to integrin β tails: a final common step in integrin activation. Science 2003; 302:103-106. (Pubitemid 37210697)
39. Petrich BG, Marchese P, Ruggeri ZM, et al. Talin is required for integrinmediated platelet function in hemostasis and thrombosis. J Exp Med 2007; 204:3103-3111.
40. Nieswandt B, Moser M, Pleines I, et al. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J Exp Med 2007; 204:3113-3118.
41. Critchley DR, Gingras AR. Talin at a glance. J Cell Sci 2008; 121:1345-1347.
42. Wegener KL, Partridge AW, Han J, et al. Structural basis of integrin activation by talin. Cell 2007; 128:171-182. (Pubitemid 46048890)
43. Petrich BG, Fogelstrand P, Partridge AW, et al. The antithrombotic potential of selective blockade of talin-dependent integrin alpha(IIb)beta(3) (platelet GPIIb-IIIa) activation. J Clin Invest 2007; 117:2250-2259.
44. Kiema T, Lad Y, Jiang P, et al. The molecular basis of filamin binding to integrins and competition with talin. Mol Cell 2006; 21:337-347. (Pubitemid 43163529)
45. Ithychanda S, Das M, Ma YQ, et al. Migfilin: a molecular switch in regulation of integrin activation. J Biol Chem 2009; 284:4713-4722. This study, together with the next reference, demonstrates the complex molecular interactions that occur to regulate integrin activation.
46. Lad Y, Jiang P, Ruskamo S, et al. Structural basis of the migfilin-filamin interaction and competition with integrin beta tails. J Biol Chem 2008; 283:35154-35163. This study, together with the preceding reference, demonstrates the complex molecular interactions that occur to regulate integrin activation.
47. Goksoy E, Ma Y-Q, Wang X, et al. Structural basis for the autoinhibition of talin in regulating integrin activation. Mol Cell 2008; 31:124-133. This study, together with the next reference, demonstrates how the intrinsic integrin-activating activity of talin is controlled by its conformation. (Pubitemid 351905930)
48. Goult BT, Bate N, Anthis NJ, et al. The structure of an interdomain complex that regulates talin activity. J Biol Chem 2009; 284:15097-15106. This study, together with the preceding reference, demonstrates how the intrinsic integrin-activating activity of talin is controlled by its conformation.
49. Han J, Lim CJ, Watanabe N, et al. Reconstructing and deconstructing agonistinduced activation of integrin alphaIIbbeta3. Curr Biol 2006; 16:1796-1806. (Pubitemid 44354146)
50. Lee HS, Lim CJ, Puzon-McLaughlin W, et al. RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences. J Biol Chem 2009; 284:5119-5127.
51. 3 (GPIIb-IIIa) in a variant of Glanzmann's thrombasthenia. Proc Natl Acad Sci USA 1992; 89:10169-10173.
52. Shi X, Ma YQ, Tu Y, et al. The mitogen inducible gene-2 (Mig-2)-integrin interaction strengthens cell-matrix adhesion and modulates cell motility. J Biol Chem 2007; 282:20455-20466.
53. Ma YQ, Qin J, Wu C, Plow EF. Kindlin-2 (Mig-2): a co-activator of beta3 integrins. J Cell Biol 2008; 181:439-446. This study, together with the following reference, establishes that kindlin-2 can cooperate with talin to induce integrin activation. This coactivator activity depends on its binding to the β subunit of integrins and involves not only on the FERM domain but also the N-terminal region of kindlin-2.
54. Montanez E, Ussar S, Schifferer M, et al. Kindlin-2 controls bidirectional signaling of integrins. Genes Dev 2008; 22:1325-1330. This study establishes that kindlin-2 can cooperate with talin to induce inside-out integrin activation and also influence outside-in signaling across integrins. This coactivator activity of kindlin depends on its binding to the β subunit of integrins. (Pubitemid 351717522)
55. Harburger DS, Bouaouina M, Calderwood DA. Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrinspecific activation effects. J Biol Chem 2009; 284:11485-11497. This study shows that both kindlin-1 and kindlin-2 bind to the cytoplasmic tails of integrin β subunits. Furthermore, influences of the kindlins on cell spreading independent of integrin binding are demonstrated.
56. Malinin NL, Zhang L, Choi J, et al. A point mutation in kindlin-3 ablates activation of three integrin subfamilies in humans. Nature Med 2009; 15:313-318. This manuscript characterizes the symptoms and blood cell responses of two patients with IADD. β1, β2 and β3 integrins do not activate on the patients' blood cells, leading to bleeding, immune and bone defects. The defect is assigned to a single point mutation in kindlin-3. Re-expression of kindlin-3 restores integrin activation on patients' cells, whereas knockdown of kindlin-3 in normal cells causes integrin activation deficiency.
57. Ussar S, Moser M, Widmaier M, et al. Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genet 2008; 4:e1000289. This study describes the phenotype of the kindlin-1-deficient mouse. The symptoms recapitulate those observed frequently in Kindler disease in humans.
58. Dowling JJ, Gibbs E, Russell M, et al. Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Cir Res 2008; 102:392-394. This study further investigates the cardiac phenotype in kindlin-2-deficient animals.
59. Dowling JJ, Vreede AP, Kim S, et al. Kindlin-2 is required for myocyte elongation and is essential for myogenesis. BMC Cell Biol 2008; 9:36. This study shows that kindlin-2 deficiency in zebrafish or mice is embryonically lethal. The phenotype implicates kindlin-2 in myogenesis.
60. ••] and shows that responses that depend on activation of the b2 integrins are blunted in the kindlin-3-deficient mice. Leukocytes in these mice and ex vivo are unable to firmly adhere and transmigrate through endothelium.
61. Kruger M, Moser M, Ussar S, et al. SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function. Cell 2008; 134:353-364. This manuscript shows that the absence of kindlin-3 in mice causes a defect in erythrocyte shape, a function that may be unrelated to its interaction with integrins. (Pubitemid 352010327)
62. Svensson L, Howarth K, McDowall A, et al. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med 2009; 15:306-312. This manuscript shows that mutations in kindlin-3 give rise to a disease in which integrins on leukocytes and platelets fail to activate. The defect is overcome by expression of kindlin-3 but not by CALDAG-GEF1.
63. Kuijpers TW, van de Vijver E, Weterman MA, et al. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 2009; 113:4740-4746. This study shows the presence of kindlin-3 mutations in LADI variant patients characterized by abnormal integrin activation on blood cells.
64. Alon R, Etzioni A. LAD-III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol 2003; 24:561-566. (Pubitemid 37205208)
65. McDowall A, Inwald D, Leitinger B, et al. A novel form of integrin dysfunction involving beta1, beta2, and beta3 integrins. J Clin Inv 2003; 111:51-60. (Pubitemid 36134848)
66. Crittenden JR, Bergmeier W, Zhang Y, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med 2004; 10:982-986. (Pubitemid 39273740)
67. Bergmeier W,Goerge T, Wang HW, et al. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest 2007; 117:1699-1707.