Structural basis of blocking integrin activation and deactivation for anti-inflammation

Journal of Biomedical Science

Motomu Shimaoka²  Hiroshi Kiyono¹  Yoshikazu Yuki³  Eun Jeong Park³ 

[1] International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Mie 514-8507, Japan;Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan

关键词: Kindlin;    Talin;    Inflammation;    Leukocyte;    Deactivation;    Activation;    Affinity;    Integrin;   

Others  :  1219620
DOI  :  10.1186/s12929-015-0159-6

 received in 2015-04-17, accepted in 2015-06-22,  发布年份 2015

【 摘 要 】

Integrins mediate leukocyte accumulation to the sites of inflammation, thereby enhancing their potential as an important therapeutic target for inflammatory disorders. Integrin activation triggered by inflammatory mediators or signaling pathway is a key step to initiate leukocyte migration to inflamed tissues; however, an appropriately regulated integrin deactivation is indispensable for maintaining productive leukocyte migration. While typical integrin antagonists that block integrin activation target the initiation of leukocyte migration, a novel class of experimental compounds has been designed to block integrin deactivation, thereby perturbing the progression of cell migration. Current review discusses the mechanisms by which integrin is activated and subsequently deactivated by focusing on its structure-function relationship.

【 授权许可】

   
2015 Park et al.

【 图 表 】

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【 参考文献 】

• [1]Anthis NJ, Haling JR, Oxley CL, Memo M, Wegener KL, Lim CJ et al.. Beta integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation. The Journal of biological chemistry. 2009; 284(52):36700-36710.
• [2]Balkow S, Heinz S, Schmidbauer P, Kolanus W, Holzmann B, Grabbe S et al.. LFA-1 activity state on dendritic cells regulates contact duration with T cells and promotes T-cell priming. Blood. 2010; 116(11):1885-1894.
• [3]Bokel C, Brown NH. Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell. 2002; 3(3):311-321.
• [4]Calderwood DA, Campbell ID, Critchley DR. Talins and kindlins: partners in integrin-mediated adhesion. Nat Rev Mol Cell Biol. 2013; 14(8):503-517.
• [5]Campbell DJ, Butcher EC. Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues. J Exp Med. 2002; 195:135-141.
• [6]Chen JF, Salas A, Springer TA. Bistable regulation of integrin adhesiveness by a bipolar metal ion cluster. Nat Struct Biol. 2003; 10:995-1001.
• [7]Chen X, Xie C, Nishida N, Li Z, Walz T, Springer TA. Requirement of open headpiece conformation for activation of leukocyte integrin alphaXbeta2. Proc Natl Acad Sci U S A. 2010; 107(33):14727-14732.
• [8]Choi WS, Rice WJ, Stokes DL, Coller BS. Three-dimensional reconstruction of intact human integrin alphaIIbbeta3: new implications for activation-dependent ligand binding. Blood. 2013; 122(26):4165-4171.
• [9]Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, Gladue RP et al.. Interferon-inducible T cell a chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med. 1998; 187:2009-2021.
• [10]Denucci CC, Mitchell JS, Shimizu Y. Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there. Crit Rev Immunol. 2009; 29(2):87-109.
• [11]Do JS, Visperas A, Freeman ML, Iwakura Y, Oukka M, Min B. Colitogenic effector T cells: roles of gut-homing integrin, gut antigen specificity and gammadelta T cells. Immunol Cell Biol. 2014; 92(1):90-98.
• [12]Doll K, Sickinger M, Seeger T. New aspects in the pathogenesis of abomasal displacement. Veterinary journal. 2009; 181(2):90-96.
• [13]Ellis SJ, Goult BT, Fairchild MJ, Harris NJ, Long J, Lobo P et al.. Talin autoinhibition is required for morphogenesis. Curr Biol. 2013; 23(18):1825-1833.
• [14]Fagerholm SC, Lek HS, Morrison VL. Kindlin-3 in the immune system. American journal of clinical and experimental immunology. 2014; 3(1):37-42.
• [15]Feagan BG, Greenberg GR, Wild G, Fedorak RN, Pare P, McDonald JW et al.. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med. 2005; 352(24):2499-2507.
• [16]Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P et al.. Natalizumab for active Crohn’s disease. N Engl J Med. 2003; 348:24-32.
• [17]Gordon FH, Hamilton MI, Donoghue S, Greenlees C, Palmer T, Rowley-Jones D et al.. A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther. 2002; 16(4):699-705.
• [18]Goult BT, Bate N, Anthis NJ, Wegener KL, Gingras AR, Patel B et al.. The structure of an interdomain complex that regulates talin activity. The Journal of biological chemistry. 2009; 284(22):15097-15106.
• [19]Goult BT, Xu XP, Gingras AR, Swift M, Patel B, Bate N et al.. Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation. J Struct Biol. 2013; 184(1):21-32.
• [20]Gozgit JM, Pentecost BT, Marconi SA, Otis CN, Wu C, Arcaro KF. Use of an aggressive MCF-7 cell line variant, TMX2-28, to study cell invasion in breast cancer. Molecular cancer research : MCR. 2006; 4(12):905-913.
• [21]Guo B, Gao J, Zhan J, Zhang H. Kindlin-2 interacts with and stabilizes EGFR and is required for EGF-induced breast cancer cell migration. Cancer Lett. 2015; 361(2):271-281.
• [22]Harburger DS, Bouaouina M, Calderwood DA. Kindlin-1 and −2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects. The Journal of biological chemistry. 2009; 284(17):11485-11497.
• [23]Herz C, Aumailley M, Schulte C, Schlotzer-Schrehardt U, Bruckner-Tuderman L, Has C. Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes. The Journal of biological chemistry. 2006; 281(47):36082-36090.
• [24]Hibbs ML, Xu H, Stacker SA, Springer TA. Regulation of adhesion to ICAM-1 by the cytoplasmic domain of LFA-1 integrin b subunit. Science. 1991; 251:1611-1613.
• [25]Huang C, Zang Q, Takagi J, Springer TA. Structural and functional studies with antibodies to the integrin b2 subunit: a model for the I-like domain. J Biol Chem. 2000; 275:21514-21524.
• [26]Humphries MJ. Integrin structure. Biochem Soc Trans. 2000; 28(4):311-339.
• [27]Huser N, Fasan A, Semmrich M, Schmidbauer P, Holzmann B, Laschinger M. Intact LFA-1 deactivation promotes T-cell activation and rejection of cardiac allograft. Int Immunol. 2010; 22(1):35-44.
• [28]Huth JR, Olejniczak ET, Mendoza R, Liang H, Harris EA, Lupher ML et al.. NMR and mutagenesis evidence for an I domain allosteric site that regulates lymphocyte function-associated antigen 1 ligand binding. Proc Natl Acad Sci U S A. 2000; 97(10):5231-5236.
• [29]Hynes RO. A reevaluation of integrins as regulators of angiogenesis. Nat Med. 2002; 8:918-921.
• [30]Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M et al.. SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature. 2011; 471(7340):637-641.
• [31]Imai Y, Park EJ, Peer D, Peixoto A, Cheng G, von Andrian UH et al.. Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates {alpha}4 integrins. Blood. 2008; 112(13):5007-5015.
• [32]Kashiwagi H, Kunishima S, Kiyomizu K, Amano Y, Shimada H, Morishita M et al.. Demonstration of novel gain-of-function mutations of alphaIIbbeta3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype. Molecular genetics & genomic medicine. 2013; 1(2):77-86.
• [33]Kempf T, Zarbock A, Widera C, Butz S, Stadtmann A, Rossaint J et al.. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med. 2011; 17(5):581-588.
• [34]Kim M, Carman CV, Springer TA. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science. 2003; 301:1720-1725.
• [35]Lai-Cheong JE, Liu L, Sethuraman G, Kumar R, Sharma VK, Reddy SR et al.. Five new homozygous mutations in the KIND1 gene in Kindler syndrome. The Journal of investigative dermatology. 2007; 127(9):2268-2270.
• [36]Lee J-O, Rieu P, Arnaout MA, Liddington R. Crystal structure of the a domain from the a subunit of integrin CR3 (CD11b/CD18). Cell. 1995; 80:631-638.
• [37]Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007; 7(9):678-689.
• [38]Lu C, Springer TA. The a subunit cytoplasmic domain regulates the assembly and adhesiveness of integrin lymphocyte function-associated antigen-1 (LFA-1). J Immunol. 1997; 159:268-278.
• [39]Lu C, Takagi J, Springer TA. Association of the membrane-proximal regions of the a and b subunit cytoplasmic domains constrains an integrin in the inactive state. J Biol Chem. 2001; 276(18):14642-14648.
• [40]Luissint AC, Nusrat A, Parkos CA. JAM-related proteins in mucosal homeostasis and inflammation. Semin Immunopathol. 2014; 36(2):211-226.
• [41]Maiguel D, Faridi MH, Wei C, Kuwano Y, Balla KM, Hernandez D et al.. Small molecule-mediated activation of the integrin CD11b/CD18 reduces inflammatory disease. Sci Signal. 2011; 4(189):ra57.
• [42]Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ et al.. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009; 15(3):313-318.
• [43]Margadant C, Sonnenberg A. Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 2010; 11(2):97-105.
• [44]McIntyre TM, Prescott SM, Weyrich AS, Zimmerman GA. Cell-cell interactions: leukocyte-endothelial interactions. Curr Opin Hematol. 2003; 10(2):150-158.
• [45]Mooren OL, Li J, Nawas J, Cooper JA. Endothelial cells use dynamic actin to facilitate lymphocyte transendothelial migration and maintain the monolayer barrier. Mol Biol Cell. 2014; 25(25):4115-4129.
• [46]Moretti FA, Moser M, Lyck R, Abadier M, Ruppert R, Engelhardt B et al.. Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells. Proc Natl Acad Sci U S A. 2013; 110(42):17005-17010.
• [47]Morin NA, Oakes PW, Hyun YM, Lee D, Chin YE, King MR et al.. Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration. J Exp Med. 2008; 205(1):195-205.
• [48]Moser M, Bauer M, Schmid S, Ruppert R, Schmidt S, Sixt M et al.. Kindlin-3 is required for beta2 integrin-mediated leukocyte adhesion to endothelial cells. Nat Med. 2009; 15(3):300-305.
• [49]Moser M, Legate KR, Zent R, Fassler R. The tail of integrins, talin, and kindlins. Science. 2009; 324(5929):895-899.
• [50]Oxley CL, Anthis NJ, Lowe ED, Vakonakis I, Campbell ID, Wegener KL. An integrin phosphorylation switch: the effect of beta3 integrin tail phosphorylation on Dok1 and talin binding. The Journal of biological chemistry. 2008; 283(9):5420-5426.
• [51]Park EJ, Mora JR, Carman CV, Chen J, Sasaki Y, Cheng G et al.. Aberrant activation of integrin alpha(4)beta(7) suppresses lymphocyte migration to the gut. J Clin Invest. 2007; 117(9):2526-2538.
• [52]Park EJ, Peixoto A, Imai Y, Goodarzi A, Cheng G, Carman CV et al.. Distinct roles for LFA-1 affinity regulation during T-cell adhesion, diapedesis, and interstitial migration in lymph nodes. Blood. 2010; 115(8):1572-1581.
• [53]Phillipson M, Heit B, Colarusso P, Liu L, Ballantyne CM, Kubes P. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med. 2006; 203(12):2569-2575.
• [54]Pouwels J, De Franceschi N, Rantakari P, Auvinen K, Karikoski M, Mattila E et al.. SHARPIN regulates uropod detachment in migrating lymphocytes. Cell reports. 2013; 5(3):619-628.
• [55]Qin J, Vinogradova O, Plow EF. Integrin bidirectional signaling: a molecular view. PLoS Biol. 2004; 2(6): Article ID e169
• [56]Rantala JK, Pouwels J, Pellinen T, Veltel S, Laasola P, Mattila E et al.. SHARPIN is an endogenous inhibitor of beta1-integrin activation. Nat Cell Biol. 2011; 13(11):1315-1324.
• [57]Ren Y, Jin H, Xue Z, Xu Q, Wang S, Zhao G, Huang J, Huang H. Kindlin-2 inhibited the growth and migration of colorectal cancer cells. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine, 2015. [Epub ahead of print] PMID:25633062.
• [58]Rui X, Mehrbod M, Van Agthoven JF, Anand S, Xiong JP, Mofrad MR et al.. The alpha-subunit regulates stability of the metal ion at the ligand-associated metal ion-binding site in beta3 integrins. The Journal of biological chemistry. 2014; 289(33):23256-23263.
• [59]Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC et al.. International efficacy of natalizumab as active Crohn’s therapy trial G. And evaluation of natalizumab as continuous therapy trial G. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005; 353(18):1912-1925.
• [60]Schmidt S, Nakchbandi I, Ruppert R, Kawelke N, Hess MW, Pfaller K et al.. Kindlin-3-mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption. J Cell Biol. 2011; 192(5):883-897.
• [61]Semmrich M, Smith A, Feterowski C, Beer S, Engelhardt B, Busch DH et al.. Importance of integrin LFA-1 deactivation for the generation of immune responses. J Exp Med. 2005; 201:1987-1998.
• [62]Sen M, Yuki K, Springer TA. An internal ligand-bound, metastable state of a leukocyte integrin, alphaXbeta2. J Cell Biol. 2013; 203(4):629-642.
• [63]Serini G, Valdembri D, Bussolino F. Integrins and angiogenesis: a sticky business. Exp Cell Res. 2006; 312(5):651-658.
• [64]Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC et al.. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes and immunity. 2007; 8(5):416-421.
• [65]Shamri R, Grabovsky V, Gauguet JM, Feigelson S, Manevich E, Kolanus W et al.. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat Immunol. 2005; 6:497-506.
• [66]Shimaoka M, Lu C, Palframan R, von Andrian UH, Takagi J, Springer TA. Reversibly locking a protein fold in an active conformation with a disulfide bond: integrin aL I domains with high affinity and antagonist activity in vivo. Proc Natl Acad Sci U S A. 2001; 98:6009-6014.
• [67]Shimaoka M, Takagi J, Springer TA. Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct. 2002; 31:485-516.
• [68]Shimaoka M, Xiao T, Liu J-H, Yang Y, Dong Y, Jun C-D et al.. Structures of the aL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell. 2003; 112:99-111.
• [69]Shulman Z, Shinder V, Klein E, Grabovsky V, Yeger O, Geron E et al.. Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin. Immunity. 2009; 30(3):384-396.
• [70]Siegel DH, Ashton GH, Penagos HG, Lee JV, Feiler HS, Wilhelmsen KC 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. 2003; 73(1):174-187.
• [71]Sin S, Bonin F, Petit V, Meseure D, Lallemand F, Bieche I et al.. Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis. J Natl Cancer Inst. 2011; 103(17):1323-1337.
• [72]Soslau G, Mason C, Lynch S, Benjamin J, Ashak D, Prakash JM et al.. Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin. Thromb Haemost. 2014; 111(1):140-153.
• [73]Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multi-step paradigm. Cell. 1994; 76:301-314.
• [74]Stanley P, Smith A, McDowall A, Nicol A, Zicha D, Hogg N. Intermediate-affinity LFA-1 binds alpha-actinin-1 to control migration at the leading edge of the T cell. The EMBO journal. 2008; 27(1):62-75.
• [75]Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S et al.. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009; 15(3):306-312.
• [76]Takagi J, Erickson HP, Springer TA. C-terminal opening mimics “inside-out” activation of integrin a5b1. Nature Struct Biol. 2001; 8(5):412-416.
• [77]Takagi J, Petre BM, Walz T, Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002; 110:599-611.
• [78]Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH et al.. International Efficacy of Natalizumab in Crohn’s Disease R. and Remission Trial G. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007; 132(5):1672-1683.
• [79]Vinogradova O, Vaynberg J, Kong X, Haas TA, Plow EF, Qin J. Membrane-mediated structural transitions at the cytoplasmic face during integrin activation. Proc Natl Acad Sci U S A. 2004; 101:4094-4099.
• [80]Vomund AN, Stuhlsatz-Krouper S, Dimitry J, Song Y, Frazier WA. A naturally occurring extracellular alpha-beta clasp contributes to stabilization of beta3 integrins in a bent, resting conformation. Biochemistry. 2008; 47(44):11616-11624.
• [81]von Andrian UH, Engelhardt B. Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med. 2003; 348(1):68-72.
• [82]von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med. 2000; 343(14):1020-1034.
• [83]Vorup-Jensen T, Ostermeier C, Shimaoka M, Hommel U, Springer TA. Structure and allosteric regulation of the aXb2 integrin I domain. Proc Natl Acad Sci U S A. 2003; 100:1873-1878.
• [84]Wang JH. Pull and push: talin activation for integrin signaling. Cell Res. 2012; 22(11):1512-1514.
• [85]Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH et al.. Structural basis of integrin activation by talin. Cell. 2007; 128(1):171-182.
• [86]Weinstein EJ, Bourner M, Head R, Zakeri H, Bauer C, Mazzarella R. URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas. Biochim Biophys Acta. 2003; 1637(3):207-216.
• [87]Wurbel MA, Malissen M, Guy-Grand D, Malissen B, Campbell JJ. Impaired accumulation of antigen-specific CD8 lymphocytes in chemokine CCL25-deficient intestinal epithelium and lamina propria. J Immunol. 2007; 178(12):7598-7606.
• [88]Xia W, Springer TA. Metal ion and ligand binding of integrin alpha5beta1. Proc Natl Acad Sci U S A. 2014; 111(50):17863-17868.
• [89]Xiong J-P, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL et al.. Crystal structure of the extracellular segment of integrin aVb3. Science. 2001; 294(5541):339-345.
• [90]Yan B, Calderwood DA, Yaspan B, Ginsberg MH. Calpain cleavage promotes talin binding to the b3 integrin cytoplasmic domain. J Biol Chem. 2001; 276:28164-28170.
• [91]Yang J, Zhu L, Zhang H, Hirbawi J, Fukuda K, Dwivedi P et al.. Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion. Nat Commun. 2014; 5:5880.
• [92]Yang W, Carman CV, Kim M, Salas A, Shimaoka M, Springer TA. A small molecule agonist of an integrin, alphaLbeta2. The Journal of biological chemistry. 2006; 281(49):37904-37912.
• [93]Yates LA, Fuzery AK, Bonet R, Campbell ID, Gilbert RJ. Biophysical analysis of Kindlin-3 reveals an elongated conformation and maps integrin binding to the membrane-distal beta-subunit NPXY motif. The Journal of biological chemistry. 2012; 287(45):37715-37731.
• [94]Ye F, Petrich BG. Kindlin: helper, co-activator, or booster of talin in integrin activation? Curr Opin Hematol. 2011; 18(5):356-360.
• [95]Zarbock A, Kempf T, Wollert KC, Vestweber D. Leukocyte integrin activation and deactivation: novel mechanisms of balancing inflammation. J Mol Med. 2012; 90(4):353-359.