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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2019

Open Access 01-12-2019 | Review

Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting

Authors: Jiansong Huang, Xia Li, Xiaofeng Shi, Mark Zhu, Jinghan Wang, Shujuan Huang, Xin Huang, Huafeng Wang, Ling Li, Huan Deng, Yulan Zhou, Jianhua Mao, Zhangbiao Long, Zhixin Ma, Wenle Ye, Jiajia Pan, Xiaodong Xi, Jie Jin

Published in: Journal of Hematology & Oncology | Issue 1/2019

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Abstract

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.
Literature
1.
2.
Staatz WD, Rajpara SM, Wayner EA, Carter WG, Santoro SA. The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen. J Cell Biol. 1989;108(5):1917–24.PubMedCrossRef
3.
Piotrowicz RS, Orchekowski RP, Nugent DJ, Yamada KY, Kunicki TJ. Glycoprotein Ic-IIa functions as an activation-independent fibronectin receptor on human platelets. J Cell Biol. 1988;106(4):1359–64.PubMedCrossRef
4.
Ill CR, Engvall E, Ruoslahti E. Adhesion of platelets to laminin in the absence of activation. J Cell Biol. 1984;99(6):2140–5.PubMedCrossRef
5.
Sonnenberg A, Modderman PW, Hogervorst F. Laminin receptor on platelets is the integrin VLA-6. Nature. 1988;336(6198):487–9.PubMedCrossRef
6.
Bennett JS, Chan C, Vilaire G, Mousa SA, DeGrado WF. Agonist-activated αvβ3 on platelets and lymphocytes binds to the matrix protein osteopontin. J Biol Chem. 1997;272(13):8137–40.PubMedCrossRef
7.
Paul BZ, Vilaire G, Kunapuli SP, Bennett JS. Concurrent signaling from Gαq- and Gαi-coupled pathways is essential for agonist-induced αvβ3 activation on human platelets. J Thromb Haemost. 2003;1(4):814–20.PubMedCrossRef
8.
Lavergne M, Janus-Bell E, Schaff M, Gachet C, Mangin PH. Platelet integrins in tumor metastasis: do they represent a therapeutic target? Cancers (Basel). 2017;9(10):133.
9.
Springer TA, Zhu J, Xiao T. Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin αIIbβ3. J Cell Biol. 2008;182(4):791–800.PubMedPubMedCentralCrossRef
10.
Nurden AT, Caen JP. An abnormal platelet glycoprotein pattern in three cases of Glanzmann’s thrombasthenia. Br J Haematol. 1974;28(2):253–60.PubMedCrossRef
11.
George JN, Caen JP, Nurden AT. Glanzmann’s thrombasthenia: the spectrum of clinical disease. Blood. 1990;75(7):1383–95.PubMed
12.
Zhou L, Jiang M, Shen H, You T, Ding Z, Cui Q, et al. Clinical and molecular insights into Glanzmann’s thrombasthenia in China. Clin Genet. 2018;94(2):213–20.PubMedCrossRef
13.
Qiao J, Wu X, Luo Q, Wei G, Xu M, Wu Y, et al. NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis. Haematologica. 2018;103(9):1568–76.PubMedPubMedCentralCrossRef
14.
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):907–14.PubMed
15.
Woods VL Jr, Wolff LE, Keller DM. Resting platelets contain a substantial centrally located pool of glycoprotein IIb-IIIa complex which may be accessible to some but not other extracellular proteins. J Biol Chem. 1986;261(32):15242–51.PubMed
16.
Wencel-Drake JD, Plow EF, Kunicki TJ, Woods VL, Keller DM, Ginsberg MH. Localization of internal pools of membrane glycoproteins involved in platelet adhesive responses. Am J Pathol. 1986;124(2):324–34.PubMedPubMedCentral
17.
Amirkhosravi A, Amaya M, Siddiqui F, Biggerstaff JP, Meyer TV, Francis JL. Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor cell-activated platelets and experimental metastasis. Platelets. 1999;10(5):285–92.PubMedCrossRef
18.
Campbell ID, Humphries MJ. Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol. 2011;3(3):a004994.
19.
20.
21.
22.
Ye F, Snider AK, Ginsberg MH. Talin and kindlin: the one-two punch in integrin activation. Front Med. 2014;8(1):6–16.PubMedCrossRef
23.
24.
Nieswandt B, Varga-Szabo D, Elvers M. Integrins in platelet activation. J Thromb Haemost. 2009;7(Suppl 1):206–9.PubMedCrossRef
25.
Goksoy E, Ma YQ, Wang X, Kong X, Perera D, Plow EF, et al. Structural basis for the autoinhibition of talin in regulating integrin activation. Mol Cell. 2008;31(1):124–33.PubMedPubMedCentralCrossRef
26.
Anthis NJ, Wegener KL, Ye F, Kim C, Goult BT, Lowe ED, et al. The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J. 2009;28(22):3623–32.PubMedPubMedCentralCrossRef
27.
Critchley DR. Cytoskeletal proteins talin and vinculin in integrin-mediated adhesion. Biochem Soc Trans. 2004;32(Pt 5):831–6.PubMedCrossRef
28.
Garcia-Alvarez B, de Pereda JM, Calderwood DA, Ulmer TS, Critchley D, Campbell ID, et al. Structural determinants of integrin recognition by talin. Mol Cell. 2003;11(1):49–58.PubMedCrossRef
29.
Di Paolo G, Pellegrini L, Letinic K, Cestra G, Zoncu R, Voronov S, et al. Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 γ by the FERM domain of talin. Nature. 2002;420(6911):85–9.PubMedCrossRef
30.
Ling K, Doughman RL, Firestone AJ, Bunce MW, Anderson RA. Type I γ phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature. 2002;420(6911):89–93.PubMedCrossRef
31.
Wegener KL, Basran J, Bagshaw CR, Campbell ID, Roberts GC, Critchley DR, et al. Structural basis for the interaction between the cytoplasmic domain of the hyaluronate receptor layilin and the talin F3 subdomain. J Mol Biol. 2008;382(1):112–26.PubMedCrossRef
32.
Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL. Interaction of focal adhesion kinase with cytoskeletal protein talin. J Biol Chem. 1995;270(28):16995–9.PubMedCrossRef
33.
Hemmings L, Rees DJ, Ohanian V, Bolton SJ, Gilmore AP, Patel B, et al. Talin contains three actin-binding sites each of which is adjacent to a vinculin-binding site. J Cell Sci. 1996;109(Pt 11):2715–26.PubMed
34.
Moes M, Rodius S, Coleman SJ, Monkley SJ, Goormaghtigh E, Tremuth L, et al. The integrin binding site 2 (IBS2) in the talin rod domain is essential for linking integrin β subunits to the cytoskeleton. J Biol Chem. 2007;282(23):17280–8.PubMedCrossRef
35.
Gingras AR, Ziegler WH, Frank R, Barsukov IL, Roberts GC, Critchley DR, et al. Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod. J Biol Chem. 2005;280(44):37217–24.PubMedCrossRef
36.
Nakazawa T, Tadokoro S, Kamae T, Kiyomizu K, Kashiwagi H, Honda S, et al. Agonist stimulation, talin-1, and kindlin-3 are crucial for αIIbβ3 activation in a human megakaryoblastic cell line, CMK. Exp Hematol. 2013;41(1):79–90.e1.PubMedCrossRef
37.
Haling JR, Monkley SJ, Critchley DR, Petrich BG. Talin-dependent integrin activation is required for fibrin clot retraction by platelets. Blood. 2011;117(5):1719–22.PubMedPubMedCentralCrossRef
38.
Kasirer-Friede A, Kang J, Kahner B, Ye F, Ginsberg MH, Shattil SJ. ADAP interactions with talin and kindlin promote platelet integrin αIIbβ3 activation and stable fibrinogen binding. Blood. 2014;123(20):3156–65.PubMedPubMedCentralCrossRef
39.
Ye F, Hu G, Taylor D, Ratnikov B, Bobkov AA, McLean MA, et al. Recreation of the terminal events in physiological integrin activation. J Cell Biol. 2010;188(1):157–73.PubMedPubMedCentralCrossRef
40.
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):28071–4.PubMedCrossRef
41.
Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, et al. Talin binding to integrin β tails: a final common step in integrin activation. Science. 2003;302(5642):103–6.PubMedCrossRef
42.
Petrich BG, Fogelstrand P, Partridge AW, Yousefi N, Ablooglu AJ, Shattil SJ, et al. The antithrombotic potential of selective blockade of talin-dependent integrin αIIbβ3 (platelet GPIIb-IIIa) activation. J Clin Invest. 2007;117(8):2250–9.PubMedPubMedCentralCrossRef
43.
Petrich BG, Marchese P, Ruggeri ZM, Spiess S, Weichert RA, Ye F, et al. Talin is required for integrin-mediated platelet function in hemostasis and thrombosis. J Exp Med. 2007;204(13):3103–11.PubMedPubMedCentralCrossRef
44.
Nieswandt B, Moser M, Pleines I, Varga-Szabo D, Monkley S, Critchley D, 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(13):3113–8.PubMedPubMedCentralCrossRef
45.
Stefanini L, Ye F, Snider AK, Sarabakhsh K, Piatt R, Paul DS, et al. A talin mutant that impairs talin-integrin binding in platelets decelerates αIIbβ3 activation without pathological bleeding. Blood. 2014;123(17):2722–31.PubMedPubMedCentralCrossRef
46.
Bledzka K, Bialkowska K, Nie H, Qin J, Byzova T, Wu C, et al. Tyrosine phosphorylation of integrin β3 regulates kindlin-2 binding and integrin activation. J Biol Chem. 2010;285(40):30370–4.PubMedPubMedCentralCrossRef
47.
Moser M, Nieswandt B, Ussar S, Pozgajova M, Fassler R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med. 2008;14(3):325–30.PubMedCrossRef
48.
49.
Montanez E, Ussar S, Schifferer M, Bosl M, Zent R, Moser M, et al. Kindlin-2 controls bidirectional signaling of integrins. Genes Dev. 2008;22(10):1325–30.PubMedPubMedCentralCrossRef
50.
Klapproth S, Moretti FA, Zeiler M, Ruppert R, Breithaupt U, Mueller S, et al. Minimal amounts of kindlin-3 suffice for basal platelet and leukocyte functions in mice. Blood. 2015;126(24):2592–600.PubMedCrossRef
51.
Gao J, Huang M, Lai J, Mao K, Sun P, Cao Z, et al. Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin. J Cell Sci. 2017;130(21):3764–75.PubMedPubMedCentralCrossRef
52.
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):11485–97.PubMedPubMedCentralCrossRef
53.
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):306–12.PubMedPubMedCentralCrossRef
54.
Moser M, Legate KR, Zent R, Fassler R. The tail of integrins, talin, and kindlins. Science. 2009;324(5929):895–9.PubMedCrossRef
55.
Lai-Cheong JE, Parsons M, McGrath JA. The role of kindlins in cell biology and relevance to human disease. Int J Biochem Cell Biol. 2010;42(5):595–603.PubMedCrossRef
56.
Meves A, Stremmel C, Gottschalk K, Fassler R. The Kindlin protein family: new members to the club of focal adhesion proteins. Trends Cell Biol. 2009;19(10):504–13.PubMedCrossRef
57.
Ussar S, Wang HV, Linder S, Fassler R, Moser M. The Kindlins: subcellular localization and expression during murine development. Exp Cell Res. 2006;312(16):3142–51.PubMedCrossRef
58.
Bialkowska K, Ma YQ, Bledzka K, Sossey-Alaoui K, Izem L, Zhang X, et al. The integrin co-activator Kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell. J Biol Chem. 2010;285(24):18640–9.PubMedPubMedCentralCrossRef
59.
Zhou C, Song S, Zhang J. A novel 3017-bp deletion mutation in the FERMT1 (KIND1) gene in a Chinese family with Kindler syndrome. Br J Dermatol. 2009;160(5):1119–22.PubMedCrossRef
60.
Techanukul T, Sethuraman G, Zlotogorski A, Horev L, Macarov M, Trainer A, et al. Novel and recurrent FERMT1 gene mutations in Kindler syndrome. Acta Derm Venereol. 2011;91(3):267–70.PubMedCrossRef
61.
Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, et al. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009;113(19):4740–6.PubMedCrossRef
62.
Nagy M, Mastenbroek TG, Mattheij NJA, de Witt S, Clemetson KJ, Kirschner J, et al. Variable impairment of platelet functions in patients with severe, genetically linked immune deficiencies. Haematologica. 2018;103(3):540–9.PubMedPubMedCentralCrossRef
63.
Rognoni E, Ruppert R, Fassler R. The kindlin family: functions, signaling properties and implications for human disease. J Cell Sci. 2016;129(1):17–27.PubMedCrossRef
64.
McDowall A, Svensson L, Stanley P, Patzak I, Chakravarty P, Howarth K, et al. Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro. Blood. 2010;115(23):4834–42.PubMedCrossRef
65.
Wang P, Zhan J, Song J, Wang Y, Fang W, Liu Z, et al. Differential expression of Kindlin-1 and Kindlin-2 correlates with esophageal cancer progression and epidemiology. Sci China Life Sci. 2017;60(11):1214–22.PubMedCrossRef
66.
Dowling JJ, Gibbs E, Russell M, Goldman D, Minarcik J, Golden JA, et al. Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circ Res. 2008;102(4):423–31.PubMedCrossRef
67.
Pluskota E, Dowling JJ, Gordon N, Golden JA, Szpak D, West XZ, et al. The integrin coactivator kindlin-2 plays a critical role in angiogenesis in mice and zebrafish. Blood. 2011;117(18):4978–87.PubMedPubMedCentralCrossRef
68.
Goult BT, Bouaouina M, Harburger DS, Bate N, Patel B, Anthis NJ, et al. The structure of the N-terminus of kindlin-1: a domain important for αIIbβ3 integrin activation. J Mol Biol. 2009;394(5):944–56.PubMedPubMedCentralCrossRef
69.
Bledzka K, Liu J, Xu Z, Perera HD, Yadav SP, Bialkowska K, et al. Spatial coordination of kindlin-2 with talin head domain in interaction with integrin β cytoplasmic tails. J Biol Chem. 2012;287(29):24585–94.PubMedPubMedCentralCrossRef
70.
Anthis NJ, Haling JR, Oxley CL, Memo M, Wegener KL, Lim CJ, et al. β Integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation. J Biol Chem. 2009;284(52):36700–10.PubMedPubMedCentralCrossRef
71.
Oxley CL, Anthis NJ, Lowe ED, Vakonakis I, Campbell ID, Wegener KL. An integrin phosphorylation switch: the effect of β3 integrin tail phosphorylation on Dok1 and talin binding. J Biol Chem. 2008;283(9):5420–6.PubMedCrossRef
72.
73.
Li H, Deng Y, Sun K, Yang H, Liu J, Wang M, et al. Structural basis of kindlin-mediated integrin recognition and activation. Proc Natl Acad Sci U S A. 2017;114(35):9349–54.PubMedPubMedCentralCrossRef
74.
Fukuda K, Bledzka K, Yang J, Perera HD, Plow EF, Qin J. Molecular basis of kindlin-2 binding to integrin-linked kinase pseudokinase for regulating cell adhesion. J Biol Chem. 2014;289(41):28363–75.PubMedPubMedCentralCrossRef
75.
Huet-Calderwood C, Brahme NN, Kumar N, Stiegler AL, Raghavan S, Boggon TJ, et al. Differences in binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation. J Cell Sci. 2014;127(Pt 19):4308–21.PubMedPubMedCentralCrossRef
76.
Kasirer-Friede A, Moran B, Nagrampa-Orje J, Swanson K, Ruggeri ZM, Schraven B, et al. ADAP is required for normal αIIbβ3 activation by VWF/GP Ib-IX-V and other agonists. Blood. 2007;109(3):1018–25.PubMedPubMedCentralCrossRef
77.
78.
Theodosiou M, Widmaier M, Bottcher RT, Rognoni E, Veelders M, Bharadwaj M, et al. Kindlin-2 cooperates with talin to activate integrins and induces cell spreading by directly binding paxillin. Elife. 2016;5:e10130.PubMedPubMedCentralCrossRef
79.
Sakata A, Ohmori T, Nishimura S, Suzuki H, Madoiwa S, Mimuro J, et al. Paxillin is an intrinsic negative regulator of platelet activation in mice. Thromb J. 2014;12(1):1.PubMedPubMedCentralCrossRef
80.
Honda S, Shirotani-Ikejima H, Tadokoro S, Maeda Y, Kinoshita T, Tomiyama Y, et al. Integrin-linked kinase associated with integrin activation. Blood. 2009;113(21):5304–13.PubMedCrossRef
81.
Shattil SJ, O’Toole T, Eigenthaler M, Thon V, Williams M, Babior BM, et al. β3-Endonexin, a novel polypeptide that interacts specifically with the cytoplasmic tail of the integrin β3 subunit. J Cell Biol. 1995;131(3):807–16.PubMedCrossRef
82.
Kashiwagi H, Schwartz MA, Eigenthaler M, Davis KA, Ginsberg MH, Shattil SJ. Affinity modulation of platelet integrin αIIbβ3 by β3-endonexin, a selective binding partner of the β3 integrin cytoplasmic tail. J Cell Biol. 1997;137(6):1433–43.PubMedPubMedCentralCrossRef
83.
Tsuboi S. Calcium integrin-binding protein activates platelet integrin αIIbβ3. J Biol Chem. 2002;277(3):1919–23.PubMedCrossRef
84.
Yuan W, Leisner TM, McFadden AW, Wang Z, Larson MK, Clark S, et al. CIB1 is an endogenous inhibitor of agonist-induced integrin αIIbβ3 activation. J Cell Biol. 2006;172(2):169–75.PubMedPubMedCentralCrossRef
85.
Larkin D, Murphy D, Reilly DF, Cahill M, Sattler E, Harriott P, et al. ICln, a novel integrin αIIbβ3-associated protein, functionally regulates platelet activation. J Biol Chem. 2004;279(26):27286–93.PubMedCrossRef
86.
Gushiken FC, Hyojeong H, Pradhan S, Langlois KW, Alrehani N, Cruz MA, et al. The catalytic subunit of protein phosphatase 1 γ regulates thrombin-induced murine platelet αIIbβ3 function. PLoS One. 2009;4(12):e8304.PubMedPubMedCentralCrossRef
87.
Ohmori T, Kashiwakura Y, Ishiwata A, Madoiwa S, Mimuro J, Honda S, et al. Vinculin activates inside-out signaling of integrin αIIbβ3 in Chinese hamster ovary cells. Biochem Biophys Res Commun. 2010;400(3):323–8.PubMedCrossRef
88.
Tucker KL, Sage T, Stevens JM, Jordan PA, Jones S, Barrett NE, et al. A dual role for integrin-linked kinase in platelets: regulating integrin function and α-granule secretion. Blood. 2008;112(12):4523–31.PubMedPubMedCentralCrossRef
89.
Jones CI, Tucker KL, Sasikumar P, Sage T, Kaiser WJ, Moore C, et al. Integrin-linked kinase regulates the rate of platelet activation and is essential for the formation of stable thrombi. J Thromb Haemost. 2014;12(8):1342–52.PubMedCrossRef
90.
Pasquet JM, Noury M, Nurden AT. Evidence that the platelet integrin αIIbβ3 is regulated by the integrin-linked kinase, ILK, in a PI3-kinase dependent pathway. Thromb Haemost. 2002;88(1):115–22.PubMed
91.
Sadoul K, Vignoud L, Mossuz P, Block MR. Proteolysis leads to the appearance of the long form of β3-endonexin in human platelets. Exp Cell Res. 2005;305(2):427–35.PubMedCrossRef
92.
Kracun D, Riess F, Kanchev I, Gawaz M, Gorlach A. The β3-integrin binding protein β3-endonexin is a novel negative regulator of hypoxia-inducible factor-1. Antioxid Redox Signal. 2014;20(13):1964–76.PubMedPubMedCentralCrossRef
93.
Naik MU, Naik TU, Summer R, Naik UP. Binding of CIB1 to the αIIb tail of αIIbβ3 is required for FAK recruitment and activation in platelets. PLoS One. 2017;12(5):e0176602.PubMedPubMedCentralCrossRef
94.
Lagarrigue F, Vikas Anekal P, Lee HS, Bachir AI, Ablack JN, Horwitz AF, et al. A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration. Nat Commun. 2015;6:8492.PubMedPubMedCentralCrossRef
95.
Mitsios JV, Prevost N, Kasirer-Friede A, Gutierrez E, Groisman A, Abrams CS, et al. What is vinculin needed for in platelets? J Thromb Haemost. 2010;8(10):2294–304.PubMedPubMedCentralCrossRef
96.
Kato A, Kawamata N, Tamayose K, Egashira M, Miura R, Fujimura T, et al. Ancient ubiquitous protein 1 binds to the conserved membrane-proximal sequence of the cytoplasmic tail of the integrin α subunits that plays a crucial role in the inside-out signaling of αIIbβ3. J Biol Chem. 2002;277(32):28934–41.PubMedCrossRef
97.
Kiema T, Lad Y, Jiang P, Oxley CL, Baldassarre M, Wegener KL, et al. The molecular basis of filamin binding to integrins and competition with talin. Mol Cell. 2006;21(3):337–47.PubMedCrossRef
98.
McCleverty CJ, Lin DC, Liddington RC. Structure of the PTB domain of tensin1 and a model for its recruitment to fibrillar adhesions. Protein Sci. 2007;16(6):1223–9.PubMedPubMedCentralCrossRef
99.
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):171–82.PubMedCrossRef
100.
Denofrio JC, Yuan W, Temple BR, Gentry HR, Parise LV. Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: potential compensation by CIB family members. Thromb Haemost. 2008;100(5):847–56.PubMedPubMedCentralCrossRef
101.
Naik MU, Nigam A, Manrai P, Millili P, Czymmek K, Sullivan M, et al. CIB1 deficiency results in impaired thrombosis: the potential role of CIB1 in outside-in signaling through integrin αIIbβ3. J Thromb Haemost. 2009;7(11):1906–14.PubMedCrossRef
102.
Izard T, Vonrhein C. Structural basis for amplifying vinculin activation by talin. J Biol Chem. 2004;279(26):27667–78.PubMedCrossRef
103.
Calderwood DA, Fujioka Y, de Pereda JM, Garcia-Alvarez B, Nakamoto T, Margolis B, et al. Integrin β cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc Natl Acad Sci U S A. 2003;100(5):2272–7.PubMedPubMedCentralCrossRef
104.
Chatterjee D, D’Souza A, Zhang Y, Bin W, Tan SM, Bhattacharjya S. Interaction analyses of 14-3-3ζ, Dok1, and phosphorylated integrin β cytoplasmic tails reveal a bi-molecular switch in integrin regulation. J Mol Biol. 2018;430(21):4419–30.PubMedCrossRef
105.
Niki M, Nayak MK, Jin H, Bhasin N, Plow EF, Pandolfi PP, et al. Dok-1 negatively regulates platelet integrin αIIbβ3 outside-in signalling and inhibits thrombosis in mice. Thromb Haemost. 2016;115(5):969–78.PubMedPubMedCentralCrossRef
106.
Hughan SC, Spring CM, Schoenwaelder SM, Sturgeon S, Alwis I, Yuan Y, et al. Dok-2 adaptor protein regulates the shear-dependent adhesive function of platelet integrin αIIbβ3 in mice. J Biol Chem. 2014;289(8):5051–60.PubMedPubMedCentralCrossRef
107.
Liu J, Das M, Yang J, Ithychanda SS, Yakubenko VP, Plow EF, et al. Structural mechanism of integrin inactivation by filamin. Nat Struct Mol Biol. 2015;22(5):383–9.PubMedPubMedCentralCrossRef
108.
Berrou E, Adam F, Lebret M, Planche V, Fergelot P, Issertial O, et al. Gain-of-function mutation in filamin A potentiates platelet integrin αIIbβ3 activation. Arterioscler Thromb Vasc Biol. 2017;37(6):1087–97.PubMedCrossRef
109.
Tadokoro S, Nakazawa T, Kamae T, Kiyomizu K, Kashiwagi H, Honda S, et al. A potential role for α-actinin in inside-out αIIbβ3 signaling. Blood. 2011;117(1):250–8.PubMedCrossRef
110.
Legate KR, Fassler R. Mechanisms that regulate adaptor binding to β-integrin cytoplasmic tails. J Cell Sci. 2009;122(Pt 2):187–98.PubMedCrossRef
111.
Shams H, Mofrad MRK. α-Actinin induces a kink in the transmembrane domain of β3-integrin and impairs activation via talin. Biophys J. 2017;113(4):948–56.PubMedPubMedCentralCrossRef
112.
Vanhoorelbeke K, Ulrichts H, Van de Walle G, Fontayne A, Deckmyn H. Inhibition of platelet glycoprotein Ib and its antithrombotic potential. Curr Pharm Des. 2007;13(26):2684–97.PubMedCrossRef
113.
114.
Severin S, Nash CA, Mori J, Zhao Y, Abram C, Lowell CA, et al. Distinct and overlapping functional roles of Src family kinases in mouse platelets. J Thromb Haemost. 2012;10(8):1631–45.PubMedPubMedCentralCrossRef
115.
Li Z, Zhang G, Liu J, Stojanovic A, Ruan C, Lowell CA, et al. An important role of the SRC family kinase Lyn in stimulating platelet granule secretion. J Biol Chem. 2010;285(17):12559–70.PubMedPubMedCentralCrossRef
116.
117.
Geue S, Walker-Allgaier B, Eissler D, Tegtmeyer R, Schaub M, Lang F, et al. Doxepin inhibits GPVI-dependent platelet Ca (2+) signaling and collagen-dependent thrombus formation. Am J Physiol Cell Physiol. 2017;312(6):C765–C74.PubMedCrossRef
118.
Suzuki-Inoue K, Inoue O, Frampton J, Watson SP. Murine GPVI stimulates weak integrin activation in PLCγ2−/− platelets: involvement of PLCγ1 and PI3-kinase. Blood. 2003;102(4):1367–73.PubMedCrossRef
119.
Ozaki Y, Asazuma N, Suzuki-Inoue K, Berndt MC. Platelet GPIb-IX-V-dependent signaling. J Thromb Haemost. 2005;3(8):1745–51.PubMedCrossRef
120.
Woulfe D, Jiang H, Mortensen R, Yang J, Brass LF. Activation of Rap1B by G(i) family members in platelets. J Biol Chem. 2002;277(26):23382–90.PubMedCrossRef
121.
Varga-Szabo D, Braun A, Nieswandt B. Calcium signaling in platelets. J Thromb Haemost. 2009;7(7):1057–66.PubMedCrossRef
122.
Cifuni SM, Wagner DD, Bergmeier W. CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin αIIbβ3 in platelets. Blood. 2008;112(5):1696–703.PubMedPubMedCentralCrossRef
123.
Piatt R, Paul DS, Lee RH, McKenzie SE, Parise LV, Cowley DO, et al. Mice expressing low levels of CalDAG-GEFI exhibit markedly impaired platelet activation with minor impact on hemostasis. Arterioscler Thromb Vasc Biol. 2016;36(9):1838–46.PubMedPubMedCentralCrossRef
124.
Kato H, Nakazawa Y, Kurokawa Y, Kashiwagi H, Morikawa Y, Morita D, et al. Human CalDAG-GEFI deficiency increases bleeding and delays αIIbβ3 activation. Blood. 2016;128(23):2729–33.PubMedCrossRef
125.
Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004;10(9):982–6.PubMedCrossRef
126.
Harper MT, Poole AW. Diverse functions of protein kinase C isoforms in platelet activation and thrombus formation. J Thromb Haemost. 2010;8(3):454–62.PubMedCrossRef
127.
Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B, Calderwood DA, et al. Reconstructing and deconstructing agonist-induced activation of integrin αIIbβ3. Curr Biol. 2006;16(18):1796–806.PubMedCrossRef
128.
Konopatskaya O, Gilio K, Harper MT, Zhao Y, Cosemans JM, Karim ZA, et al. PKCα regulates platelet granule secretion and thrombus formation in mice. J Clin Invest. 2009;119(2):399–407.PubMedPubMedCentral
129.
Chrzanowska-Wodnicka M, Smyth SS, Schoenwaelder SM, Fischer TH, White GC 2nd. Rap1b is required for normal platelet function and hemostasis in mice. J Clin Invest. 2005;115(3):680–7.PubMedPubMedCentralCrossRef
130.
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):5119–27.PubMedPubMedCentralCrossRef
131.
Stritt S, Wolf K, Lorenz V, Vogtle T, Gupta S, Bosl MR, et al. Rap1-GTP-interacting adaptor molecule (RIAM) is dispensable for platelet integrin activation and function in mice. Blood. 2015;125(2):219–22.PubMedPubMedCentralCrossRef
132.
Watanabe N, Bodin L, Pandey M, Krause M, Coughlin S, Boussiotis VA, et al. Mechanisms and consequences of agonist-induced talin recruitment to platelet integrin αIIbβ3. J Cell Biol. 2008;181(7):1211–22.PubMedPubMedCentralCrossRef
133.
Zhu L, Yang J, Bromberger T, Holly A, Lu F, Liu H, et al. Structure of Rap1b bound to talin reveals a pathway for triggering integrin activation. Nat Commun. 2017;8(1):1744.PubMedPubMedCentralCrossRef
134.
Lagarrigue F, Gingras AR, Paul DS, Valadez AJ, Cuevas MN, Sun H, et al. Rap1 binding to the talin 1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv. 2018;2(18):2358–68.PubMedPubMedCentralCrossRef
135.
Srinivasan S, Schiemer J, Zhang X, Chishti AH, Le Breton GC. Gα13 switch region 2 binds to the talin head domain and activates αIIbβ3 integrin in human platelets. J Biol Chem. 2015;290(41):25129–39.PubMedPubMedCentralCrossRef
136.
Wee JL, Jackson DE. The Ig-ITIM superfamily member PECAM-1 regulates the “outside-in” signaling properties of integrin αIIbβ3 in platelets. Blood. 2005;106(12):3816–23.PubMedCrossRef
137.
Wong C, Liu Y, Yip J, Chand R, Wee JL, Oates L, et al. CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo. Blood. 2009;113(8):1818–28.PubMedCrossRef
138.
Jones CI, Sage T, Moraes LA, Vaiyapuri S, Hussain U, Tucker KL, et al. Platelet endothelial cell adhesion molecule-1 inhibits platelet response to thrombin and von Willebrand factor by regulating the internalization of glycoprotein Ib via AKT/glycogen synthase kinase-3/dynamin and integrin αIIbβ3. Arterioscler Thromb Vasc Biol. 2014;34(9):1968–76.PubMedCrossRef
139.
Newland SA, Macaulay IC, Floto AR, de Vet EC, Ouwehand WH, Watkins NA, et al. The novel inhibitory receptor G6B is expressed on the surface of platelets and attenuates platelet function in vitro. Blood. 2007;109(11):4806–9.PubMedCrossRef
140.
Geer MJ, van Geffen JP, Gopalasingam P, Vogtle T, Smith CW, Heising S, et al. Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis. Blood. 2018;132(13):1413–25.PubMedPubMedCentralCrossRef
141.
Mazharian A, Wang YJ, Mori J, Bem D, Finney B, Heising S, et al. Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function. Sci Signal. 2012;5(248):ra78.PubMedPubMedCentralCrossRef
142.
Hu M, Liu P, Liu Y, Yue M, Wang Y, Wang S, et al. Platelet Shp2 negatively regulates thrombus stability under high shear stress. J Thromb Haemost. 2019;17(1):220–31.PubMedCrossRef
143.
Naik UP, Ehrlich YH, Kornecki E. Mechanisms of platelet activation by a stimulatory antibody: cross-linking of a novel platelet receptor for monoclonal antibody F11 with the FcγRII receptor. Biochem J. 1995;310(Pt 1):155–62.PubMedPubMedCentralCrossRef
144.
Nasdala I, Wolburg-Buchholz K, Wolburg H, Kuhn A, Ebnet K, Brachtendorf G, et al. A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J Biol Chem. 2002;277(18):16294–303.PubMedCrossRef
145.
Stalker TJ, Wu J, Morgans A, Traxler EA, Wang L, Chatterjee MS, et al. Endothelial cell specific adhesion molecule (ESAM) localizes to platelet-platelet contacts and regulates thrombus formation in vivo. J Thromb Haemost. 2009;7(11):1886–96.PubMedPubMedCentralCrossRef
146.
Sobocka MB, Sobocki T, Babinska A, Hartwig JH, Li M, Ehrlich YH, et al. Signaling pathways of the F11 receptor (F11R; a.k.a. JAM-1, JAM-A) in human platelets: F11R dimerization, phosphorylation and complex formation with the integrin GPIIIa. J Recept Signal Transduct Res. 2004;24(1–2):85–105.PubMedCrossRef
147.
Naik MU, Caplan JL, Naik UP. Junctional adhesion molecule-A suppresses platelet integrin αIIbβ3 signaling by recruiting Csk to the integrin-c-Src complex. Blood. 2014;123(9):1393–402.PubMedPubMedCentralCrossRef
148.
Naik MU, Stalker TJ, Brass LF, Naik UP. JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets. Blood. 2012;119(14):3352–60.PubMedPubMedCentralCrossRef
149.
Orlowski E, Chand R, Yip J, Wong C, Goschnick MW, Wright MD, et al. A platelet tetraspanin superfamily member, CD151, is required for regulation of thrombus growth and stability in vivo. J Thromb Haemost. 2009;7(12):2074–84.PubMedCrossRef
150.
Lau LM, Wee JL, Wright MD, Moseley GW, Hogarth PM, Ashman LK, et al. The tetraspanin superfamily member CD151 regulates outside-in integrin αIIbβ3 signaling and platelet function. Blood. 2004;104(8):2368–75.PubMedCrossRef
151.
Goschnick MW, Lau LM, Wee JL, Liu YS, Hogarth PM, Robb LM, et al. Impaired “outside-in” integrin αIIbβ3 signaling and thrombus stability in TSSC6-deficient mice. Blood. 2006;108(6):1911–8.PubMedCrossRef
152.
Israels SJ, McMillan-Ward EM. CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen. Thromb Haemost. 2005;93(2):311–8.PubMedCrossRef
153.
Uchtmann K, Park ER, Bergsma A, Segula J, Edick MJ, Miranti CK. Homozygous loss of mouse tetraspanin CD82 enhances integrin αIIbβ3 expression and clot retraction in platelets. Exp Cell Res. 2015;339(2):261–9.PubMedCrossRef
154.
Indig FE, Diaz-Gonzalez F, Ginsberg MH. Analysis of the tetraspanin CD9-integrin αIIbβ3 (GPIIb-IIIa) complex in platelet membranes and transfected cells. Biochem J. 1997;327(Pt 1):291–8.PubMedPubMedCentralCrossRef
155.
Israels SJ, McMillan-Ward EM, Easton J, Robertson C, McNicol A. CD63 associates with the αIIbβ3 integrin-CD9 complex on the surface of activated platelets. Thromb Haemost. 2001;85(1):134–41.PubMedCrossRef
156.
Wright MD, Geary SM, Fitter S, Moseley GW, Lau LM, Sheng KC, et al. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol Cell Biol. 2004;24(13):5978–88.PubMedPubMedCentralCrossRef
157.
Makkawi M, Moheimani F, Alserihi R, Howells D, Wright M, Ashman L, et al. A complementary role for tetraspanin superfamily member CD151 and ADP purinergic P2Y12 receptor in platelets. Thromb Haemost. 2015;114(5):1004–19.PubMedCrossRef
158.
Makkawi M, Howells D, Wright MD, Jackson DE. A complementary role for tetraspanin superfamily member TSSC6 and ADP purinergic P2Y12 receptor in platelets. Thromb Res. 2018;161:12–21.PubMedCrossRef
159.
Mangin PH, Kleitz L, Boucheix C, Gachet C, Lanza F. CD9 negatively regulates integrin αIIbβ3 activation and could thus prevent excessive platelet recruitment at sites of vascular injury. J Thromb Haemost. 2009;7(5):900–2.PubMedCrossRef
160.
Saller F, Burnier L, Schapira M, Angelillo-Scherrer A. Role of the growth arrest-specific gene 6 (gas6) product in thrombus stabilization. Blood Cells Mol Dis. 2006;36(3):373–8.PubMedCrossRef
161.
Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Schaeffer P, et al. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest. 2005;115(2):237–46.PubMedPubMedCentralCrossRef
162.
Gould WR, Baxi SM, Schroeder R, Peng YW, Leadley RJ, Peterson JT, et al. Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. J Thromb Haemost. 2005;3(4):733–41.PubMedCrossRef
163.
Cosemans JM, Van Kruchten R, Olieslagers S, Schurgers LJ, Verheyen FK, Munnix IC, et al. Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization. J Thromb Haemost. 2010;8(8):1797–808.PubMedCrossRef
164.
Law LA, Graham DK, Di Paola J, Branchford BR. GAS6/TAM pathway signaling in hemostasis and thrombosis. Front Med (Lausanne). 2018;5:137.CrossRef
165.
Wannemacher KM, Zhu L, Jiang H, Fong KP, Stalker TJ, Lee D, et al. Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4D. Blood. 2010;116(25):5707–15.PubMedPubMedCentralCrossRef
166.
Nanda N, Andre P, Bao M, Clauser K, Deguzman F, Howie D, et al. Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling. Blood. 2005;106(9):3028–34.PubMedCrossRef
167.
Hofmann S, Braun A, Pozgaj R, Morowski M, Vogtle T, Nieswandt B. Mice lacking the SLAM family member CD84 display unaltered platelet function in hemostasis and thrombosis. PLoS One. 2014;9(12):e115306.PubMedPubMedCentralCrossRef
168.
Gong H, Shen B, Flevaris P, Chow C, Lam SC, Voyno-Yasenetskaya TA, et al. G protein subunit Gα13 binds to integrin αIIbβ3 and mediates integrin “outside-in” signaling. Science. 2010;327(5963):340–3.PubMedPubMedCentralCrossRef
169.
Moers A, Nieswandt B, Massberg S, Wettschureck N, Gruner S, Konrad I, et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat Med. 2003;9(11):1418–22.PubMedCrossRef
170.
Xiang B, Zhang G, Ye S, Zhang R, Huang C, Liu J, et al. Characterization of a novel integrin binding protein, VPS33B, which is important for platelet activation and in vivo thrombosis and hemostasis. Circulation. 2015;132(24):2334–44.PubMedPubMedCentralCrossRef
171.
Obergfell A, Judd BA, del Pozo MA, Schwartz MA, Koretzky GA, Shattil SJ. The molecular adapter SLP-76 relays signals from platelet integrin αIIbβ3 to the actin cytoskeleton. J Biol Chem. 2001;276(8):5916–23.PubMedCrossRef
172.
Leon C, Eckly A, Hechler B, Aleil B, Freund M, Ravanat C, et al. Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion. Blood. 2007;110(9):3183–91.PubMedCrossRef
173.
Deshmukh L, Gorbatyuk V, Vinogradova O. Integrin β3 phosphorylation dictates its complex with the Shc phosphotyrosine-binding (PTB) domain. J Biol Chem. 2010;285(45):34875–84.PubMedPubMedCentralCrossRef
174.
Law DA, Nannizzi-Alaimo L, Phillips DR. Outside-in integrin signal transduction. αIIbβ3-(GP IIb IIIa) tyrosine phosphorylation induced by platelet aggregation. J Biol Chem. 1996;271(18):10811–5.PubMedCrossRef
175.
Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets. Blood. 2008;112(7):2780–6.PubMedPubMedCentralCrossRef
176.
Takizawa H, Nishimura S, Takayama N, Oda A, Nishikii H, Morita Y, et al. Lnk regulates integrin αIIbβ3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo. J Clin Invest. 2010;120(1):179–90.PubMedCrossRef
177.
Xu Y, Ouyang X, Yan L, Zhang M, Hu Z, Gu J, et al. Sin1 (stress-activated protein kinase-interacting protein) regulates ischemia-induced microthrombosis through integrin αIIbβ3-mediated outside-in signaling and hypoxia responses in platelets. Arterioscler Thromb Vasc Biol. 2018;38(12):2793–805.
178.
179.
Tsai HJ, Huang CL, Chang YW, Huang DY, Lin CC, Cooper JA, et al. Disabled-2 is required for efficient hemostasis and platelet activation by thrombin in mice. Arterioscler Thromb Vasc Biol. 2014;34(11):2404–12.PubMedPubMedCentralCrossRef
180.
Shcherbina A, Cooley J, Lutskiy MI, Benarafa C, Gilbert GE, Remold-O’Donnell E. WASP plays a novel role in regulating platelet responses dependent on αIIbβ3 integrin outside-in signalling. Br J Haematol. 2010;148(3):416–27.PubMedCrossRef
181.
Shen B, Zhao X, O’Brien KA, Stojanovic-Terpo A, Delaney MK, Kim K, et al. A directional switch of integrin signalling and a new anti-thrombotic strategy. Nature. 2013;503(7474):131–5.PubMedPubMedCentralCrossRef
182.
Clements JL, Lee JR, Gross B, Yang B, Olson JD, Sandra A, et al. Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. J Clin Invest. 1999;103(1):19–25.PubMedPubMedCentralCrossRef
183.
Judd BA, Myung PS, Leng L, Obergfell A, Pear WS, Shattil SJ, et al. Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through αIIbβ3 and collagen receptors. Proc Natl Acad Sci U S A. 2000;97(22):12056–61.PubMedPubMedCentralCrossRef
184.
Zhang H, Berg JS, Li Z, Wang Y, Lang P, Sousa AD, et al. Myosin-X provides a motor-based link between integrins and the cytoskeleton. Nat Cell Biol. 2004;6(6):523–31.PubMedCrossRef
185.
Donner L, Gremer L, Ziehm T, Gertzen CGW, Gohlke H, Willbold D, et al. Relevance of N-terminal residues for amyloid-β binding to platelet integrin αIIbβ3, integrin outside-in signaling and amyloid-β fibril formation. Cell Signal. 2018;50:121–30.PubMedCrossRef
186.
Verhaar R, Dekkers DW, De Cuyper IM, Ginsberg MH, de Korte D, Verhoeven AJ. UV-C irradiation disrupts platelet surface disulfide bonds and activates the platelet integrin αIIbβ3. Blood. 2008;112(13):4935–9.PubMedPubMedCentralCrossRef
187.
188.
Gao C, Boylan B, Fang J, Wilcox DA, Newman DK, Newman PJ. Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling. Blood. 2011;117(18):4946–52.PubMedPubMedCentralCrossRef
189.
Kiouptsi K, Gambaryan S, Walter E, Walter U, Jurk K, Reinhardt C. Hypoxia impairs agonist-induced integrin αIIbβ3 activation and platelet aggregation. Sci Rep. 2017;7(1):7621.PubMedPubMedCentralCrossRef
190.
Unsworth AJ, Kriek N, Bye AP, Naran K, Sage T, Flora GD, et al. PPARγ agonists negatively regulate αIIbβ3 integrin outside-in signaling and platelet function through up-regulation of protein kinase A activity. J Thromb Haemost. 2017;15(2):356–69.PubMedPubMedCentralCrossRef
191.
Tseng WL, Huang CL, Chong KY, Liao CH, Stern A, Cheng JC, et al. Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen. Cell Mol Life Sci. 2010;67(4):641–53.PubMedCrossRef
192.
Gowert NS, Kruger I, Klier M, Donner L, Kipkeew F, Gliem M, et al. Loss of Reelin protects mice against arterial thrombosis by impairing integrin activation and thrombus formation under high shear conditions. Cell Signal. 2017;40:210–21.PubMedCrossRef
193.
Zhao Z, Wu Y, Zhou J, Chen F, Yang A, Essex DW. The transmembrane protein disulfide isomerase TMX1 negatively regulates platelet responses. Blood. 2019;133(3):246–51.PubMedCrossRef
194.
Arias-Salgado EG, Lizano S, Shattil SJ, Ginsberg MH. Specification of the direction of adhesive signaling by the integrin β cytoplasmic domain. J Biol Chem. 2005;280(33):29699–707.PubMedCrossRef
195.
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 U S A. 2003;100(23):13298–302.PubMedPubMedCentralCrossRef
196.
Huang J, Shi X, Xi W, Liu P, Long Z, Xi X. Evaluation of targeting c-Src by the RGT-containing peptide as a novel antithrombotic strategy. J Hematol Oncol. 2015;8:62.PubMedPubMedCentralCrossRef
197.
Su X, Mi J, Yan J, Flevaris P, Lu Y, Liu H, et al. RGT, a synthetic peptide corresponding to the integrin β3 cytoplasmic C-terminal sequence, selectively inhibits outside-in signaling in human platelets by disrupting the interaction of integrin αIIbβ3 with Src kinase. Blood. 2008;112(3):592–602.PubMedPubMedCentralCrossRef
198.
Ablooglu AJ, Kang J, Petrich BG, Ginsberg MH, Shattil SJ. Antithrombotic effects of targeting αIIbβ3 signaling in platelets. Blood. 2009;113(15):3585–92.PubMedPubMedCentralCrossRef
199.
Arias-Salgado EG, Haj F, Dubois C, Moran B, Kasirer-Friede A, Furie BC, et al. PTP-1B is an essential positive regulator of platelet integrin signaling. J Cell Biol. 2005;170(5):837–45.PubMedPubMedCentralCrossRef
200.
Obergfell A, Eto K, Mocsai A, Buensuceso C, Moores SL, Brugge JS, et al. Coordinate interactions of Csk, Src, and Syk kinases with αIIbβ3 initiate integrin signaling to the cytoskeleton. J Cell Biol. 2002;157(2):265–75.PubMedPubMedCentralCrossRef
201.
202.
Pearce AC, McCarty OJ, Calaminus SD, Vigorito E, Turner M, Watson SP. Vav family proteins are required for optimal regulation of PLCγ2 by integrin αIIbβ3. Biochem J. 2007;401(3):753–61.PubMedPubMedCentralCrossRef
203.
Law DA, Nannizzi-Alaimo L, Ministri K, Hughes PE, Forsyth J, Turner M, et al. Genetic and pharmacological analyses of Syk function in αIIbβ3 signaling in platelets. Blood. 1999;93(8):2645–52.PubMed
204.
Poole A, Gibbins JM, Turner M, van Vugt MJ, van de Winkel JG, Saito T, et al. The Fc receptor γ-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen. EMBO J. 1997;16(9):2333–41.PubMedPubMedCentralCrossRef
205.
Clark EA, Shattil SJ, Brugge JS. Regulation of protein tyrosine kinases in platelets. Trends Biochem Sci. 1994;19(11):464–9.PubMedCrossRef
206.
Beck S, Leitges M, Stegner D. Protein kinase Cι/λ is dispensable for platelet function in thrombosis and hemostasis in mice. Cell Signal. 2017;38:223–9.PubMedCrossRef
207.
Yoshioka A, Shirakawa R, Nishioka H, Tabuchi A, Higashi T, Ozaki H, et al. Identification of protein kinase Cα as an essential, but not sufficient, cytosolic factor for Ca2+-induced α- and dense-core granule secretion in platelets. J Biol Chem. 2001;276(42):39379–85.PubMedCrossRef
208.
Tabuchi A, Yoshioka A, Higashi T, Shirakawa R, Nishioka H, Kita T, et al. Direct demonstration of involvement of protein kinase Cα in the Ca2+-induced platelet aggregation. J Biol Chem. 2003;278(29):26374–9.PubMedCrossRef
209.
Buensuceso CS, Obergfell A, Soriani A, Eto K, Kiosses WB, Arias-Salgado EG, et al. Regulation of outside-in signaling in platelets by integrin-associated protein kinase Cβ. J Biol Chem. 2005;280(1):644–53.PubMedCrossRef
210.
Pula G, Schuh K, Nakayama K, Nakayama KI, Walter U, Poole AW. PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. Blood. 2006;108(13):4035–44.PubMedCrossRef
211.
Chari R, Getz T, Nagy B Jr, Bhavaraju K, Mao Y, Bynagari YS, et al. Protein kinase Cδ differentially regulates platelet functional responses. Arterioscler Thromb Vasc Biol. 2009;29(5):699–705.PubMedPubMedCentralCrossRef
212.
Soriani A, Moran B, de Virgilio M, Kawakami T, Altman A, Lowell C, et al. A role for PKCθ in outside-in αIIbβ3 signaling. J Thromb Haemost. 2006;4(3):648–55.PubMedCrossRef
213.
Hall KJ, Harper MT, Gilio K, Cosemans JM, Heemskerk JW, Poole AW. Genetic analysis of the role of protein kinase Cθ in platelet function and thrombus formation. PLoS One. 2008;3(9):e3277.PubMedPubMedCentralCrossRef
214.
Maxwell MJ, Yuan Y, Anderson KE, Hibbs ML, Salem HH, Jackson SP. SHIP1 and Lyn kinase negatively regulate integrin αIIbβ3 signaling in platelets. J Biol Chem. 2004;279(31):32196–204.PubMedCrossRef
215.
Battram AM, Durrant TN, Agbani EO, Heesom KJ, Paul DS, Piatt R, et al. The phosphatidylinositol 3,4,5-trisphosphate (PI (3,4,5) P3) binder Rasa3 regulates phosphoinositide 3-kinase (PI3K)-dependent integrin αIIbβ3 outside-in signaling. J Biol Chem. 2017;292(5):1691–704.PubMedCrossRef
216.
Sun DS, Lo SJ, Lin CH, Yu MS, Huang CY, Chen YF, et al. Calcium oscillation and phosphatidylinositol 3-kinase positively regulate integrin αIIbβ3-mediated outside-in signaling. J Biomed Sci. 2005;12(2):321–33.PubMedCrossRef
217.
Lian L, Wang Y, Draznin J, Eslin D, Bennett JS, Poncz M, et al. The relative role of PLCβ and PI3Kγ in platelet activation. Blood. 2005;106(1):110–7.PubMedPubMedCentralCrossRef
218.
Cosemans JM, Munnix IC, Wetzker R, Heller R, Jackson SP, Heemskerk JW. Continuous signaling via PI3K isoforms β and γ is required for platelet ADP receptor function in dynamic thrombus stabilization. Blood. 2006;108(9):3045–52.PubMedCrossRef
219.
Laurent PA, Hechler B, Solinhac R, Ragab A, Cabou C, Anquetil T, et al. Impact of PI3Kα (phosphoinositide 3-kinase α) inhibition on hemostasis and thrombosis. Arterioscler Thromb Vasc Biol. 2018;38(9):2041–53.PubMedCrossRef
220.
Buitrago L, Langdon WY, Sanjay A, Kunapuli SP. Tyrosine phosphorylated c-Cbl regulates platelet functional responses mediated by outside-in signaling. Blood. 2011;118(20):5631–40.PubMedPubMedCentralCrossRef
221.
Cipolla L, Consonni A, Guidetti G, Canobbio I, Okigaki M, Falasca M, et al. The proline-rich tyrosine kinase Pyk2 regulates platelet integrin αIIbβ3 outside-in signaling. J Thromb Haemost. 2013;11(2):345–56.PubMedCrossRef
222.
Canobbio I, Cipolla L, Consonni A, Momi S, Guidetti G, Oliviero B, et al. Impaired thrombin-induced platelet activation and thrombus formation in mice lacking the Ca (2+)-dependent tyrosine kinase Pyk2. Blood. 2013;121(4):648–57.PubMedCrossRef
223.
Laurent PA, Severin S, Hechler B, Vanhaesebroeck B, Payrastre B, Gratacap MP. Platelet PI3Kβ and GSK3 regulate thrombus stability at a high shear rate. Blood. 2015;125(5):881–8.PubMedCrossRef
224.
Prevost N, Mitsios JV, Kato H, Burke JE, Dennis EA, Shimizu T, et al. Group IVA cytosolic phospholipase A2 (cPLA2α) and integrin αIIbβ3 reinforce each other’s functions during αIIbβ3 signaling in platelets. Blood. 2009;113(2):447–57.PubMedPubMedCentralCrossRef
225.
Wong DA, Kita Y, Uozumi N, Shimizu T. Discrete role for cytosolic phospholipase A (2) α in platelets: studies using single and double mutant mice of cytosolic and group IIA secretory phospholipase A (2). J Exp Med. 2002;196(3):349–57.PubMedPubMedCentralCrossRef
226.
Khatlani T, Pradhan S, Da Q, Shaw T, Buchman VL, Cruz MA, et al. A novel interaction of the catalytic subunit of protein phosphatase 2A with the adaptor protein CIN85 suppresses phosphatase activity and facilitates platelet outside-in αIIbβ3 integrin signaling. J Biol Chem. 2016;291(33):17360–8.PubMedPubMedCentralCrossRef
227.
Pleines I, Hagedorn I, Gupta S, May F, Chakarova L, van Hengel J, et al. Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis. Blood. 2012;119(4):1054–63.PubMedCrossRef
228.
Pleines I, Elvers M, Strehl A, Pozgajova M, Varga-Szabo D, May F, et al. Rac1 is essential for phospholipase C-γ2 activation in platelets. Pflugers Arch. 2009;457(5):1173–85.PubMedCrossRef
229.
Akbar H, Shang X, Perveen R, Berryman M, Funk K, Johnson JF, et al. Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation. PLoS One. 2011;6(7):e22117.PubMedPubMedCentralCrossRef
230.
Giordano A, Musumeci G, D’Angelillo A, Rossini R, Zoccai GB, Messina S, et al. Effects of glycoprotein IIb/IIIa antagonists: anti platelet aggregation and beyond. Curr Drug Metab. 2016;17(2):194–203.PubMedCrossRef
231.
Schwarz M, Nordt T, Bode C, Peter K. The GP IIb/IIIa inhibitor abciximab (c7E3) inhibits the binding of various ligands to the leukocyte integrin Mac-1 (CD11b/CD18, alphaMbeta2). Thromb Res. 2002;107(3–4):121–8.PubMedCrossRef
232.
Scarborough RM, Naughton MA, Teng W, Rose JW, Phillips DR, Nannizzi L, et al. Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa. J Biol Chem. 1993;268(2):1066–73.PubMed
233.
Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, et al. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators Lancet. 1994;343(8902):881–6.PubMedCrossRef
234.
Stoffer K, Shah S. Abciximab. StatPearls, Vol. Treasure Island (FL); 2018.
235.
De Luca G, Savonitto S, van’t Hof AW, Suryapranata H. Platelet GP IIb-IIIa receptor antagonists in primary angioplasty: back to the future. Drugs. 2015;75(11):1229–53.PubMedCrossRef
236.
Cannon CP, McCabe CH, Wilcox RG, Langer A, Caspi A, Berink P, et al. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation. 2000;102(2):149–56.PubMedCrossRef
237.
238.
239.
Xie Z, Cao C, Feng S, Huang J, Li Z. Progress in the research of GPIIb/IIIa antagonists. Future Med Chem. 2015;7(9):1149–71.PubMedCrossRef
240.
Jamasbi J, Ayabe K, Goto S, Nieswandt B, Peter K, Siess W. Platelet receptors as therapeutic targets: past, present and future. Thromb Haemost. 2017;117(7):1249–57.PubMedCrossRef
241.
Estevez B, Shen B, Du X. Targeting integrin and integrin signaling in treating thrombosis. Arterioscler Thromb Vasc Biol. 2015;35(1):24–9.PubMedCrossRef
242.
Bassler N, Loeffler C, Mangin P, Yuan Y, Schwarz M, Hagemeyer CE, et al. A mechanistic model for paradoxical platelet activation by ligand-mimetic αIIbβ3 (GPIIb/IIIa) antagonists. Arterioscler Thromb Vasc Biol. 2007;27(3):e9–15.
243.
Wang X, Palasubramaniam J, Gkanatsas Y, Hohmann JD, Westein E, Kanojia R, et al. Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets. Circ Res. 2014;114(7):1083–93.PubMedCrossRef
244.
Fuentes RE, Zaitsev S, Ahn HS, Hayes V, Kowalska MA, Lambert MP, et al. A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation. J Clin Invest. 2016;126(2):483–94.PubMedCrossRef
245.
Hohmann JD, Wang X, Krajewski S, Selan C, Haller CA, Straub A, et al. Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding? Blood. 2013;121(16):3067–75.PubMedPubMedCentralCrossRef
246.
Liu TD, Ren SH, Ding X, Xie ZL, Kong Y. A short half-life αIIbβ3 antagonist ANTP266 reduces thrombus formation. Int J Mol Sci. 2018;19(8):2306.
247.
Li J, Vootukuri S, Shang Y, Negri A, Jiang JK, Nedelman M, et al. RUC-4: a novel αIIbβ3 antagonist for prehospital therapy of myocardial infarction. Arterioscler Thromb Vasc Biol. 2014;34(10):2321–9.
248.
Law DA, DeGuzman FR, Heiser P, Ministri-Madrid K, Killeen N, Phillips DR. Integrin cytoplasmic tyrosine motif is required for outside-in αIIbβ3 signalling and platelet function. Nature. 1999;401(6755):808–11.
249.
Schroder J, Lullmann-Rauch R, Himmerkus N, Pleines I, Nieswandt B, Orinska Z, et al. Deficiency of the tetraspanin CD63 associated with kidney pathology but normal lysosomal function. Mol Cell Biol. 2009;29(4):1083–94.PubMedCrossRef
250.
Senis YA, Tomlinson MG, Ellison S, Mazharian A, Lim J, Zhao Y, et al. The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis. Blood. 2009;113(20):4942–54.PubMedPubMedCentralCrossRef
251.
Wang L, Wu Y, Zhou J, Ahmad SS, Mutus B, Garbi N, et al. Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the αIIbβ3 integrin. Blood. 2013;122(22):3642–50.PubMedPubMedCentralCrossRef
252.
Fan X, Wang C, Shi P, Gao W, Gu J, Geng Y, et al. Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice. Blood Adv. 2018;2(12):1439–48.PubMedPubMedCentralCrossRef
253.
Chen X, Fan X, Tan J, Shi P, Wang X, Wang J, et al. Palladin is involved in platelet activation and arterial thrombosis. Thromb Res. 2017;149:1–8.PubMedCrossRef
254.
Chen X, Zhang Y, Wang Y, Li D, Zhang L, Wang K, et al. PDK1 regulates platelet activation and arterial thrombosis. Blood. 2013;121(18):3718–26.PubMedCrossRef
255.
Weng Z, Li D, Zhang L, Chen J, Ruan C, Chen G, et al. PTEN regulates collagen-induced platelet activation. Blood. 2010;116(14):2579–81.PubMedCrossRef
256.
McCarty OJ, Larson MK, Auger JM, Kalia N, Atkinson BT, Pearce AC, et al. Rac1 is essential for platelet lamellipodia formation and aggregate stability under flow. J Biol Chem. 2005;280(47):39474–84.PubMedPubMedCentralCrossRef
257.
Sladojevic N, Oh GT, Kim HH, Beaulieu LM, Falet H, Kaminski K, et al. Decreased thromboembolic stroke but not atherosclerosis or vascular remodelling in mice with ROCK2-deficient platelets. Cardiovasc Res. 2017;113(11):1307–17.PubMedPubMedCentralCrossRef
258.
Graff J, Klinkhardt U, Westrup D, Kirchmaier CM, Breddin HK, Harder S. Pharmacodynamic characterization of the interaction between the glycoprotein IIb/IIIa inhibitor YM337 and unfractionated heparin and aspirin in humans. Br J Clin Pharmacol. 2003;56(3):321–6.PubMedPubMedCentralCrossRef
259.
Greenberg HE, Wissel P, Barrett J, Barchowsky A, Gould R, Farrell D, et al. Antiplatelet effects of MK-852, a platelet fibrinogen receptor antagonist, in healthy volunteers. J Clin Pharmacol. 2000;40(5):496–507.PubMedCrossRef
260.
Collen D, Lu HR, Stassen JM, Vreys I, Yasuda T, Bunting S, et al. Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis. Thromb Haemost. 1994;71(1):95–102.PubMedCrossRef
261.
Michaelis W, Turlapaty P, Gray J, Fiske WD, Faulkner E, Kornhauser D, et al. Pharmacodynamics and pharmacokinetics of DMP 728, a platelet GPIIb/IIIa antagonist, in healthy subjects. Clin Pharmacol Ther. 1998;63(3):384–92.PubMedCrossRef
262.
Hartman GD, Egbertson MS, Halczenko W, Laswell WL, Duggan ME, Smith RL, et al. Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors. J Med Chem. 1992;35(24):4640–2.PubMedCrossRef
263.
Starnes HB, Patel AA, Stouffer GA. Optimal use of platelet glycoprotein IIb/IIIa receptor antagonists in patients undergoing percutaneous coronary interventions. Drugs. 2011;71(15):2009–30.PubMedCrossRef
264.
Storey RF, Wilcox RG, Heptinstall S. Differential effects of glycoprotein IIb/IIIa antagonists on platelet microaggregate and macroaggregate formation and effect of anticoagulant on antagonist potency. Implications for assay methodology and comparison of different antagonists. Circulation. 1998;98(16):1616–21.PubMedCrossRef
265.
Brugts JJ, Mercado N, Hu S, Guarneri M, Price M, Schatz R, et al. Relation of periprocedural bleeding complications and long-term outcome in patients undergoing percutaneous coronary revascularization (from the Evaluation of Oral Xemilofiban in Controlling Thrombotic Events [EXCITE] Trial). Am J Cardiol. 2009;103(7):917–22.PubMedCrossRef
266.
Smith EE, Cannon CP, Murphy S, Feske SK, Schwamm LH. Risk factors for stroke after acute coronary syndromes in the orbofiban in patients with unstable coronary syndromes--thrombolysis in myocardial infarction (OPUS-TIMI) 16 study. Am Heart J. 2006;151(2):338–44.PubMedCrossRef
267.
Wong CK, Newby LK, Bhapker MV, Aylward PE, Pfisterer M, Alexander KP, et al. Use of evidence-based medicine for acute coronary syndromes in the elderly and very elderly: insights from the Sibrafiban vs aspirin to yield maximum protection from ischemic heart events postacute cOroNary sYndromes trials. Am Heart J. 2007;154(2):313–21.PubMedCrossRef
268.
Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, Graffagnino C, et al. Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation. 2003;108(4):399–406.PubMedCrossRef
269.
Murphy J, Wright RS, Gussak I, Williams B, Daly RN, Cain VA, et al. The use of roxifiban (DMP754), a novel oral platelet glycoprotein IIb/IIIa receptor inhibitor, in patients with stable coronary artery disease. Am J Cardiovasc Drugs. 2003;3(2):101–12.PubMedCrossRef
270.
Damiano BP, Mitchell JA, Giardino E, Corcoran T, Haertlein BJ, de Garavilla L, et al. Antiplatelet and antithrombotic activity of RWJ-53308, a novel orally active glycoprotein IIb/IIIa antagonist. Thromb Res. 2001;104(2):113–26.PubMedCrossRef
271.
Savi P, Badorc A, Lale A, Bordes MF, Bornia J, Labouret C, et al. SR 121787, a new orally active fibrinogen receptor antagonist. Thromb Haemost. 1998;80(3):469–76.PubMedCrossRef
272.
Giugliano RP, McCabe CH, Sequeira RF, Frey MJ, Henry TD, Piana RN, et al. First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: results of the TIMI 15A and 15B trials. Am Heart J. 2000;140(1):81–93.PubMedCrossRef
273.
Zhu J, Choi WS, McCoy JG, Negri A, Zhu J, Naini S, et al. Structure-guided design of a high-affinity platelet integrin αIIbβ3 receptor antagonist that disrupts Mg (2)(+) binding to the MIDAS. Sci Transl Med. 2012;4(125):125ra32.
274.
Polishchuk PG, Samoylenko GV, Khristova TM, Krysko OL, Kabanova TA, Kabanov VM, et al. Design, virtual screening, and synthesis of antagonists of αIIbβ3 as antiplatelet agents. J Med Chem. 2015;58(19):7681–94.
275.
Ziegler M, Hohmann JD, Searle AK, Abraham MK, Nandurkar HH, Wang X, et al. A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury. Eur Heart J. 2018;39(2):111–6.PubMed
Metadata
Title
Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting
Authors
Jiansong Huang
Xia Li
Xiaofeng Shi
Mark Zhu
Jinghan Wang
Shujuan Huang
Xin Huang
Huafeng Wang
Ling Li
Huan Deng
Yulan Zhou
Jianhua Mao
Zhangbiao Long
Zhixin Ma
Wenle Ye
Jiajia Pan
Xiaodong Xi
Jie Jin
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0709-6

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