1. Vivier, E. and M. Daeron, Immunoreceptor tyrosine-based inhibition motifs. Immunol Today, 1997. 18(6): p. 286-91.
2. Burshtyn, D.N., et al., A novel phosphotyrosine motif with a critical amino acid at position -2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1. J Biol Chem, 1997. 272(20): p. 13066-72.
3. Daeron, M., Intracytoplasmic sequences involved in the biological properties of low-affinity receptors for IgG expressed by murine macrophages. Braz J Med Biol Res, 1995. 28(3): p. 263-74.
4. D'Ambrosio, D., et al., Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by Fc gamma RIIB1. Science, 1995. 268(5208): p. 293-7.
5. Reth, M., Antigen receptor tail clue. Nature, 1989. 338(6214): p. 383-4.
6. Cambier, J.C., New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL). Immunol Today, 1995. 16(2): p. 110.
7. Hughes, C.E., et al., Critical Role for an acidic amino acid region in platelet signaling by the HemITAM (hemi-immunoreceptor tyrosine-based activation motif) containing receptor CLEC-2 (C-type lectin receptor-2). J Biol Chem, 2013. 288(7): p. 5127-35.
8. Amigorena, S., et al., Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science, 1992. 256(5065): p. 1808-12.
9. Muta, T., et al., A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. Nature, 1994. 369(6478): p. 340.
10. Daeron, M., et al., The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. Immunity, 1995. 3(5): p. 635-46.
11. Newman, P.J., Switched at birth: a new family for PECAM-1. J Clin Invest, 1999. 103(1): p. 5-9.
12. Coxon, C.H., M.J. Geer, and Y.A. Senis, ITIM receptors: more than just inhibitors of platelet activation. Blood, 2017. 129(26): p. 3407-3418.
13. Sidorenko, S.P. and E.A. Clark, The dual-function CD150 receptor subfamily: the viral attraction. Nat Immunol, 2003. 4(1): p. 19-24.
14. Gibbins, J.M., The negative regulation of platelet function: extending the role of the ITIM. Trends Cardiovasc Med, 2002. 12(5): p. 213-9.
15. Washington, A.V., et al., A TREM family member, TLT-1, is found exclusively in the alpha-granules of megakaryocytes and platelets. Blood, 2004. 104(4): p. 1042-7.
16. Steevels, T.A., et al., Co-expression of the collagen receptors leukocyte-associated immunoglobulin-like receptor-1 and glycoprotein VI on a subset of megakaryoblasts. Haematologica, 2010. 95(12): p. 2005-12.
17. Senis, Y.A., et al., A comprehensive proteomics and genomics analysis reveals novel transmembrane proteins in human platelets and mouse megakaryocytes including G6b-B, a novel immunoreceptor tyrosine-based inhibitory motif protein. Mol Cell Proteomics, 2007. 6(3): p. 548-64.
18. Suzuki-Inoue, K., et al., Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling. J Biol Chem, 2002. 277(24): p. 21561-6.
19. Locke, D., et al., Lipid rafts orchestrate signaling by the platelet receptor glycoprotein VI. J Biol Chem, 2002. 277(21): p. 18801-9.
20. Wonerow, P., et al., Differential role of glycolipid-enriched membrane domains in glycoprotein VI- and integrin-mediated phospholipase Cgamma2 regulation in platelets. Biochem J, 2002. 364(Pt 3): p. 755-65.
21. Pasquet, J.M., et al., LAT is required for tyrosine phosphorylation of phospholipase cgamma2 and platelet activation by the collagen receptor GPVI. Mol Cell Biol, 1999. 19(12): p. 8326-34.
- 14 -
22. Billadeau, D.D. and P.J. Leibson, ITAMs versus ITIMs: striking a balance during cell regulation. J Clin Invest, 2002. 109(2): p. 161-8.
23. Moraes, L.A., et al., Platelet endothelial cell adhesion molecule-1 regulates collagen-stimulated platelet function by modulating the association of phosphatidylinositol 3-kinase with Grb-2-associated binding protein-1 and linker for activation of T cells. J Thromb Haemost, 2010. 8(11): p. 2530-41.
24. Wee, J.L. and D.E. Jackson, The Ig-ITIM superfamily member PECAM-1 regulates the "outside-in" signaling properties of integrin alpha(IIb)beta3 in platelets. Blood, 2005. 106(12): p. 3816-23.
25. Mazharian, A., et al., Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function. Blood, 2013. 121(20): p. 4205-20.
26. Yip, J., et al., CEACAM1 regulates integrin alphaIIbbeta3-mediated functions in platelets. Platelets, 2016. 27(2): p. 168-77.
27. Alshahrani, M.M., et al., CEACAM2 positively regulates integrin alphaIIbbeta3-mediated platelet functions. Platelets, 2016. 27(8): p. 743-750.
28. Stefanini, L. and W. Bergmeier, Negative regulators of platelet activation and adhesion. J Thromb Haemost, 2018. 16(2): p. 220-230.
29. Newman, P.J., et al., PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science, 1990. 247(4947): p. 1219-22.
30. Stockinger, H., et al., Molecular characterization and functional analysis of the leukocyte surface protein CD31. J Immunol, 1990. 145(11): p. 3889-97.
31. Albelda, S.M., et al., EndoCAM: a novel endothelial cell-cell adhesion molecule. J Cell Biol, 1990. 110(4): p. 1227-37.
32. Burkhart, J.M., et al., The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood, 2012. 120(15): p. e73-82.
33. Zeiler, M., M. Moser, and M. Mann, Copy number analysis of the murine platelet proteome spanning the complete abundance range. Mol Cell Proteomics, 2014. 13(12): p. 3435-45.
34. Novinska, M., et al., Chapter 11—Pecam-1 Platelets. 2007, Academic Press.
35. Jones, C.I., et al., PECAM-1 expression and activity negatively regulate multiple platelet signaling pathways. FEBS Lett, 2009. 583(22): p. 3618-24.
36. Patil, S., D.K. Newman, and P.J. Newman, Platelet endothelial cell adhesion molecule-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood, 2001. 97(6): p. 1727-32.
37. Falati, S., et al., Platelet PECAM-1 inhibits thrombus formation in vivo. Blood, 2006. 107(2): p. 535-41.
38. Kirschbaum, N.E., R.J. Gumina, and P.J. Newman, Organization of the gene for human platelet/endothelial cell adhesion molecule-1 shows alternatively spliced isoforms and a functionally complex cytoplasmic domain. Blood, 1994. 84(12): p. 4028-37.
39. Bergom, C., et al., An alternatively spliced isoform of PECAM-1 is expressed at high levels in human and murine tissues, and suggests a novel role for the C-terminus of PECAM-1 in cytoprotective signaling. J Cell Sci, 2008. 121(Pt 8): p. 1235-42.
40. Newton, J.P., et al., CD31 (PECAM-1) exists as a dimer and is heavily N-glycosylated. Biochem Biophys Res Commun, 1999. 261(2): p. 283-91.
41. Newman, P.J. and D.K. Newman, Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology. Arterioscler Thromb Vasc Biol, 2003. 23(6): p. 953-64.
42. Jackson, D.E., K.R. Kupcho, and P.J. Newman, Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of platelet/endothelial cell adhesion molecule-1 (PECAM-1) that are required for the cellular association and activation of the protein-tyrosine phosphatase, SHP-2. J Biol Chem, 1997. 272(40): p. 24868-75.
- 15 -
43. Paddock, C., et al., Residues within a lipid-associated segment of the PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood, 2011. 117(22): p. 6012-23.
44. Osawa, M., et al., Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) in mechanically stimulated vascular endothelial cells. Eur J Cell Biol, 1997. 72(3): p. 229-37.
45. Cao, M.Y., et al., Regulation of mouse PECAM-1 tyrosine phosphorylation by the Src and Csk families of protein-tyrosine kinases. J Biol Chem, 1998. 273(25): p. 15765-72.
46. Sun, Q.H., et al., Individually distinct Ig homology domains in PECAM-1 regulate homophilic binding and modulate receptor affinity. J Biol Chem, 1996. 271(19): p. 11090-8.
47. Privratsky, J.R., et al., Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity. J Cell Sci, 2011. 124(Pt 9): p. 1477-85.
48. Sun, J., et al., Platelet endothelial cell adhesion molecule-1 (PECAM-1) homophilic adhesion is mediated by immunoglobulin-like domains 1 and 2 and depends on the cytoplasmic domain and the level of surface expression. J Biol Chem, 1996. 271(31): p. 18561-70.
49. Newton, J.P., et al., Residues on both faces of the first immunoglobulin fold contribute to homophilic binding sites of PECAM-1/CD31. J Biol Chem, 1997. 272(33): p. 20555-63.
50. Paddock, C., et al., Structural basis for PECAM-1 homophilic binding. Blood, 2016. 127(8): p. 1052-61.
51. Lee, C., et al., NEU1 sialidase regulates the sialylation state of CD31 and disrupts CD31-driven capillary-like tube formation in human lung microvascular endothelia. J Biol Chem, 2014. 289(13): p. 9121-35.
52. Lertkiatmongkol, P., et al., The Role of Sialylated Glycans in Human Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1)-mediated Trans Homophilic Interactions and Endothelial Cell Barrier Function. J Biol Chem, 2016. 291(50): p. 26216-26225.
53. DeLisser, H.M., et al., Platelet/endothelial cell adhesion molecule-1 (CD31)-mediated cellular aggregation involves cell surface glycosaminoglycans. J Biol Chem, 1993. 268(21): p. 16037-46.
54. Buckley, C.D., et al., Identification of alpha v beta 3 as a heterotypic ligand for CD31/PECAM-1. J Cell Sci, 1996. 109 ( Pt 2): p. 437-45.
55. Piali, L., et al., CD31/PECAM-1 is a ligand for alpha v beta 3 integrin involved in adhesion of leukocytes to endothelium. J Cell Biol, 1995. 130(2): p. 451-60.
56. Deaglio, S., et al., Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J Immunol, 1998. 160(1): p. 395-402.
57. Kuckleburg, C.J. and P.J. Newman, Neutrophil proteinase 3 acts on protease-activated receptor-2 to enhance vascular endothelial cell barrier function. Arterioscler Thromb Vasc Biol, 2013. 33(2): p. 275-84.
58. Sachs, U.J., et al., The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31). J Biol Chem, 2007. 282(32): p. 23603-12.
59. Mori, J., et al., G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2. J Biol Chem, 2008. 283(51): p. 35419-27.
60. de Vet, E.C., B. Aguado, and R.D. Campbell, G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2. J Biol Chem, 2001. 276(45): p. 42070-6.
61. Senis, Y.A., et al., Proteomic analysis of integrin alphaIIbbeta3 outside-in signaling reveals Src-kinase-independent phosphorylation of Dok-1 and Dok-3 leading to SHIP-1 interactions. J Thromb Haemost, 2009. 7(10): p. 1718-26.
62. Mazharian, A., et al., Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function. Sci Signal, 2012. 5(248): p. ra78.
- 16 -
63. Vogtle, T., et al., Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. Elife, 2019. 8.
64. de Vet, E.C., et al., The cell surface receptor G6b, a member of the immunoglobulin superfamily, binds heparin. FEBS Lett, 2005. 579(11): p. 2355-8.
65. Gashaw, I., et al., What makes a good drug target? Drug Discov Today, 2011. 16(23-24): p. 1037-43.
66. Sardjono, C.T., et al., Palmitoylation at Cys595 is essential for PECAM-1 localisation into membrane microdomains and for efficient PECAM-1-mediated cytoprotection. Thromb Haemost, 2006. 96(6): p. 756-66.
67. Rathore, V., et al., PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets. Blood, 2003. 102(10): p. 3658-64.
68. Crockett, J., D.K. Newman, and P.J. Newman, PECAM-1 functions as a negative regulator of laminin-induced platelet activation. J Thromb Haemost, 2010. 8(7): p. 1584-93.
69. Jones, C.I., 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 alphaIIbbeta3. Arterioscler Thromb Vasc Biol, 2014. 34(9): p. 1968-76.
70. Dhanjal, T.S., et al., Minimal regulation of platelet activity by PECAM-1. Platelets, 2007. 18(1): p. 56-67.
71. Jones, K.L., et al., Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions. Blood, 2001. 98(5): p. 1456-63.
72. Cicmil, M., et al., Platelet endothelial cell adhesion molecule-1 signaling inhibits the activation of human platelets. Blood, 2002. 99(1): p. 137-44.
73. Gurbel, P.A., et al., State of the art: Oral antiplatelet therapy. JRSM Cardiovasc Dis, 2016. 5: p. 2048004016652514.
74. Yeung, J. and M. Holinstat, Newer agents in antiplatelet therapy: a review. J Blood Med, 2012. 3: p. 33-42.
75. Jones, C.I., et al., Endogenous inhibitory mechanisms and the regulation of platelet function. Methods Mol Biol, 2012. 788: p. 341-66.
76. Novinska, M.S., et al., The alleles of PECAM-1. Gene, 2006. 376(1): p. 95-101.
77. Li, G., et al., Platelet endothelial cell adhesion molecule-1 gene 125C/G polymorphism is associated with deep vein thrombosis. Mol Med Rep, 2015. 12(2): p. 2203-10.
78. Dhanjal, T.S., et al., A novel role for PECAM-1 in megakaryocytokinesis and recovery of platelet counts in thrombocytopenic mice. Blood, 2007. 109(10): p. 4237-44.
79. Mahooti, S., et al., PECAM-1 (CD31) expression modulates bleeding time in vivo. Am J Pathol, 2000. 157(1): p. 75-81.
80. Newland, S.A., et al., The novel inhibitory receptor G6B is expressed on the surface of platelets and attenuates platelet function in vitro. Blood, 2007. 109(11): p. 4806-9.
81. Hofmann, I., et al., Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice. Blood, 2018. 132(13): p. 1399-1412.
82. Gurevich, E.V. and V.V. Gurevich, Therapeutic potential of small molecules and engineered proteins. Handb Exp Pharmacol, 2014. 219: p. 1-12.
83. Buchwald, P., Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life, 2010. 62(10): p. 724-31.
84. Faulds, D. and E.M. Sorkin, Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischaemic heart disease. Drugs, 1994. 48(4): p. 583-98.
85. Chames, P., et al., Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol, 2009. 157(2): p. 220-33.
86. Nurbhai, S., et al., Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients. Sci Rep, 2019. 9(1): p. 14042.
87. Duggan, S., Caplacizumab: First Global Approval. Drugs, 2018. 78(15): p. 1639-1642.
- 17 -
88. Tiede, C., et al., Affimer proteins are versatile and renewable affinity reagents. Elife, 2017. 6.
89. Kearney, K.J., et al., Affimer proteins as a tool to modulate fibrinolysis, stabilize the blood clot, and reduce bleeding complications. Blood, 2019. 133(11): p. 1233-1244.
90. Ungerer, M., et al., Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation, 2011. 123(17): p. 1891-9.
91. Lebozec, K., et al., Design, development and characterization of ACT017, a humanized Fab that blocks platelet's glycoprotein VI function without causing bleeding risks. MAbs, 2017. 9(6): p. 945-958.
92. Voors-Pette, C., et al., Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol, 2019. 39(5): p. 956-964.