Boundary Events: Contact-Dependent and Contact-Facilitated Signaling between Platelets

Lawrence F. Brass; Timothy J. Stalker; Li Zhu; Boxun Lu; Donna S. Woulfe; Nicolas Prevost

doi:10.1055/s-2004-833475

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2004; 30(4): 399-410
DOI: 10.1055/s-2004-833475

Boundary Events: Contact-Dependent and Contact-Facilitated Signaling between Platelets

Lawrence F. Brass¹ ^, ² , Timothy J. Stalker² , Li Zhu² , Boxun Lu² , Donna S. Woulfe² , Nicolas Prevost²

¹Professor of Medicine and Pharmacology, and the Center for Experimental Therapeutics at the University of Pennsylvania, Philadelphia, Pennsylvania
²Departments of Medicine and Pharmacology, and the Center for Experimental Therapeutics at the University of Pennsylvania, Philadelphia, Pennsylvania

Abstract

The theme of this review is that formation of a stable hemostatic plug requires adhesive interactions and signaling events that continue beyond the initial phases of platelet aggregation. These interactions and events are facilitated and, in some cases made possible, by the persistent close contacts between platelets that can only occur after the onset of aggregation. The molecules that are involved include integrins, cell adhesion molecules, receptor tyrosine kinases, and ligands that are either attached to or shed from the surface of activated platelets. The picture that emerges is one in which events after aggregation are nearly as complex as those that precede aggregation and the initiation of platelet plug formation.

KEYWORDS

Platelet activation - cell adhesion molecules - receptor tyrosine kinases - integrins - Eph kinases - contact-dependent signaling - outside-in signaling

Volltext

Referenzen

REFERENCES

1 Humbert M, Nurden P, Bihour C et al.. Ultrastructural studies of platelet aggregates from human subjects receiving clopidogrel and from a patient with an inherited defect of an ADP-dependent pathway of platelet activation. Arterioscler Thromb Vasc Biol. 1996; 16 1532-1543
2 White J G. Interaction of membrane systems in blood platelets. Am J Pathol. 1972; 66 295-312
3 White J G. Platelet membrane ultrastructure and its changes during platelet activation. Prog Clin Biol Res. 1988; 283 1-32
4 Skaer R J, Emmines J P, Skaer H B. The fine structure of cell contacts in platelet aggregation. J Ultrastruct Res. 1979; 69 28-42
5 Payrastre B, Missy K, Trumel C, Bodin S, Plantavid M, Chap H. The integrin alphaIIb/beta3 in human platelet signal transduction. Biochem Pharmacol. 2000; 60 1069-1074
6 Philips D R, Prasad K SS, Manganello J, Bao M, Nannizzi-Alaimo L. Integrin tyrosine phosphorylation in platelet signaling. Curr Opin Cell Biol. 2001; 13 546-554
7 Phillips D R, Nannizzi-Alamio L, Prasad K SS. Beta3 tyrosine phosphorylation in alphaIIbbeta3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling. Thromb Haemost. 2001; 86 246-258
8 Obergfell A, Eto K, Mocsai A et al.. Coordinate interactions of Csk, Src and Syk kinases with alphaIIbbeta3 initiate integrin signaling to the cytoskeleton. J Cell Biol. 2002; 157 265-275
9 Guinebault C, Payrastre B, Racaud-Sultan C et al.. Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85alpha with actin filaments and focal adhesion kinase. J Cell Biol. 1995; 129 831-842
10 Shattil S J, O'Toole T, Eigenthaler M et al.. Beta3-endonexin, a novel polypeptide that interacts specifically with the cytoplasmic tail of the integrin beta3 subunit. J Cell Biol. 1995; 131 807-816
11 Naik U P, Patel P M, Parise L V. Identification of a novel calcium-binding protein that interacts with the integrin alphaIIb cytoplasmic domain. J Biol Chem. 1997; 272 4651-4654
12 Shock D D, Naik U P, Brittain J E, Alahari S K, Sondek J, Parise L V. Calcium-dependent properties of CIB binding to the integrin alphaIIb cytoplasmic domain and translocation to the platelet cytoskeleton. Biochem J. 1999; 342 729-735
13 Calderwood D A, Zent R, Grant R, Rees D J, Hynes R O, Ginsberg M H. The talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J Biol Chem. 1999; 274 28071-28074
14 Gao J, Zoller K E, Ginsberg M H, Brugge J S, Shattil S J. Regulation of the pp72syk protein tyrosine kinase by platelet integrin alphaIIbbeta3. EMBO J. 1997; 16 6414-6425
15 Woodside D G, Obergfell A, Leng L et al.. Activation of Syk protein tyrosine kinase through interaction with integrin beta cytoplasmic domains. Curr Biol. 2001; 11 1799-1804
16 Jenkins A L, Nannizzi-Alaimo L, Silver D et al.. Tyrosine phosphorylation of the beta3 cytoplasmic domain mediates integrin-cytoskeletal interactions. J Biol Chem. 1998; 273 13878-13885
17 Cowan K J, Law D A, Phillips D R. Identification of Shc as the primary protein binding to the tyrosine-phosphorylated beta3 subunit of alphaIIbbeta3 during outside-in integrin platelet signaling. J Biol Chem. 2000; 275 36423-36429
18 Tadokoro S, Shattil S J, Eto K et al.. Talin binding to integrin beta tails: a final common step in integrin activation. Science. 2003; 302 103-106
19 Law D A, DeGuzman F R, Heiser P, Ministri-Madrid K, Killeen N, Phillips D R. Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signaling and platelet function. Nature. 1999; 401 808-811
20 Elrod J W, Park J H, Oshima T, Sharp C D, Minagar A, Alexander J S. Expression of junctional proteins in human platelets. Platelets. 2003; 14 247-251
21 Muller W A. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 2003; 24 327-334
22 Bazzoni G. The JAM family of junctional adhesion molecules. Curr Opin Cell Biol. 2003; 15 525-530
23 Ostermann G, Weber K S, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3 151-158
24 Santoso S, Sachs U J, Kroll H et al.. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med. 2002; 196 679-691
25 Kornecki E, Walkowiak B, Naik U P, Ehrlich Y H. Activation of human platelets by a stimulatory monoclonal antibody. J Biol Chem. 1990; 265 10042-10048
26 Naik U P, Ehrlich Y H, Kornecki E. Mechanisms of platelet activation by a stimulatory antibody: cross-linking of a novel platelet receptor for monoclonal antibody F11 with the Fc gamma RII receptor. Biochem J. 1995; 310(pt 1) 155-162
27 Babinska A, Kedees M H, Athar H et al.. F11-receptor (F11R/JAM) mediates platelet adhesion to endothelial cells: role in inflammatory thrombosis. Thromb Haemost. 2002; 88 843-850
28 Ozaki H, Ishii K, Arai H et al.. Junctional adhesion molecule (JAM) is phosphorylated by protein kinase C upon platelet activation. Biochem Biophys Res Commun. 2000; 276 873-878
29 Hirata K, Ishida T, Penta K et al.. Cloning of an immunoglobulin family adhesion molecule selectively expressed by endothelial cells. J Biol Chem. 2001; 276 16223-16231
30 Nasdala I, Wolburg-Buchholz K, Wolburg H et al.. A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J Biol Chem. 2002; 277 16294-16303
31 Ishida T, Kundu R K, Yang E, Hirata K, Ho Y D, Quertermous T. Targeted disruption of endothelial cell-selective adhesion molecule inhibits angiogenic processes in vitro and in vivo. J Biol Chem. 2003; 278 34598-34604
32 Scott J L, Dunn S M, Jin B et al.. Characterization of a novel membrane glycoprotein involved in platelet activation. J Biol Chem. 1989; 264 13475-13482
33 Kojima H, Kanada H, Shimizu S et al.. CD226 mediates platelet and megakaryocytic cell adhesion to vascular endothelial cells. J Biol Chem. 2003; 278 36748-36753
34 Shibuya A, Lanier L L, Phillips J H. Protein kinase C is involved in the regulation of both signaling and adhesion mediated by DNAX accessory molecule-1 receptor. J Immunol. 1998; 161 1671-1676
35 Bottino C, Castriconi R, Pende D et al.. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med. 2003; 198 557-567
36 Prevost N, Woulfe D, Tanaka T, Brass L F. Interactions between Eph kinases and ephrins provide a novel mechanism to support platelet aggregation once cell-to-cell contact has occurred. Proc Natl Acad Sci USA. 2002; 99 9219-9224
37 Prevost N, Fortna R, Tognolini M, Woulfe D, Wu J, Brass L F. Contact-dependent signaling by Eph kinases and ephrins promotes the late phases of platelet activation, including clot retraction. Blood. 2002; 100 477a
38 Woulfe D, Prevost N, Jiang H, Tognolini M, Fortna R, Brass L F. Eph receptor-ephrin interactions contribute to the tyrosine phosphorylation of the cytoplasmic domain of the beta subunit of alphaIIbbeta3 during platelet aggregation. Blood. 2002; 100 477a
39 Prevost N, Woulfe D S, Tognolini M et al.. Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion and aggregation via effector pathways that do not require phosphorylation of ephrinB1. Blood. 2004; 103 1348-1355
40 Gale N W, Holland S J, Valenzuela D M et al.. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron. 1996; 17 9-19
41 Klein R. Excitatory Eph receptors and adhesive ephrin ligands. Curr Opin Cell Biol. 2001; 13 196-203
42 Dodelet V C, Pasquale E B. Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene. 2000; 19 5614-5619
43 Gerety S S, Wang H U, Chen Z-F, Anderson D J. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell. 1999; 4 403-414
44 Adams R H, Wilkinson G A, Weiss C et al.. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis and sprouting angiogenesis. Genes Dev. 1999; 13 295-306
45 Adams R H, Klein R. Eph receptors and ephrin ligands: essential mediators of vascular development. Trends Cardiovasc Med. 2000; 10 183-188
46 Himanen J P, Henkemeyer M, Nikolov D B. Crystal structure of the ligand binding domain of the receptor tyrosine kinase EphB2. Nature. 1998; 396 486-491
47 Toth J, Cutforth T, Gelinas A D, Bethoney K A, Bard J, Harrison C J. Crystal structure of an ephrin ectodomain. Dev Cell. 2001; 1 83-92
48 Kalo M S, Yu H H, Pasquale E B. In vivo tyrosine phosphorylation sites of activated ephrin-B1 and EphB2 from neural tissues. J Biol Chem. 2001; 276 38940-38948
49 Torres R, Firestein B L, Dong H L et al.. PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron. 1998; 21 1453-1463
50 Lin D, Gish G D, Songyang Z, Pawson T. The carboxyl terminus of B class ephrins constitutes a PDZ binding motif. J Biol Chem. 1999; 274 3726-3733
51 Bruckner K, Pablo Labrador J, Scheiffele P, Herb A, Seeburg P H, Klein R. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron. 1999; 22 511-524
52 Della Rocca G J, Van Biesen T, Daaka Y, Luttrell D K, Luttrell L M, Lefkowitz R J. Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors-convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. J Biol Chem. 1997; 272 19125-19132
53 Himanen J P, Rajashankar K R, Lackmann M, Cowan C A, Henkemeyer M, Nikolov D B. Crystal structure of an Eph receptor-ephrin complex. Nature. 2001; 414 933-938
54 Huynh-Do U, Stein E, Lane A A, Liu H, Cerretti D P, Daniel T O. Surface densities of ephrin-B1 determine EphB1-coupled activation if cell attachment through alphavbeta3 and alpha5beta1 integrins. EMBO J. 1999; 18 2165-2173
55 Holland S J, Gale N W, Gish G D et al.. Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. EMBO J. 1997; 16 3877-3888
56 Hock B, Bohme B, Karn T et al.. PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor. Proc Natl Acad Sci USA. 1998; 95 9779-9784
57 Dodelet V C, Pazzagli C, Zisch A H, Hauser C A, Pasquale E B. A novel signaling intermediate, SHEP1, directly couples Eph receptors to R-Ras and Rap1A. J Biol Chem. 1999; 274 31941-31946
58 Pandey A, Duan H, Dixit V M. Characterization of a novel src-like adapter protein that associates with the Eck receptor tyrosine kinase. J Biol Chem. 1995; 270 19201-19204
59 Cowan C A, Henkemeyer M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature. 2001; 413 174-179
60 Birgbauer E, Cowan C A, Sretavan D W, Henkemeyer M. Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. Development. 2000; 127 1231-1241
61 Buchert M, Schneider S, Meskenaite V et al.. The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialized sites of cell-cell contact in the brain. J Cell Biol. 1999; 144 361-371
62 Holland S J, Gale N W, Mbamalu G, Vancopoulos G D, Henkemeyer M, Pawson T. Bidirectional signaling through the the EPH-family receptor Nuk and its transmembrane ligands. Nature. 1996; 383 722-725
63 Palmer A, Zimer M, Erdmann K S et al.. Ephrin B phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Mol Cell. 2002; 9 725-737
64 Xu Z, Kwok-On L, Zhou H-M, Lin S-C, Ip N Y. Ephrin-B1 reverse signaling activates JNK through a novel mechanism that is independent of tyrosine phosphorylation. J Biol Chem. 2003; 278 24767-24775
65 Schultz J, Ponting C P, Hofmann K, Bork P. SAM as a protein interaction domain involved in developmental regulation. Protein Sci. 1997; 6 249-253
66 Thanos C D, Goodwill K E, Bowie J U. Oligomeric structure of the human Ephb2 receptor SAM domain. Science. 1999; 283 833-836
67 Stapleton D, Balan L, Pawson T, Sicheri F. The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization. Nat Struct Biol. 1999; 6 44-49
68 Smalla M, Schmieder P, Kelly M et al.. Solution structure of the receptor tyrosine kinase EphB2 SAM domain and identification of two distinct homotypic interaction sites. Protein Sci. 1999; 8 1954-1961
69 Wilkinson D G. Eph receptors and ephrins: regulators of guidance and assembly. Int Rev Cytol. 2000; 196 177-244
70 Gale N W, Yancopoulos G D. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 1999; 13 1055-1066
71 Kullander K, Klein R. Mechanisms and function of Eph and ephrin signaling. Nat Rev Mol Cell Biol. 2002; 3 475-486
72 Sakano S, Serizawa R, Inada T et al.. Characterization of a ligand for receptor protein-tyrosine kinase HTK expressed in immature hematopoietic cells. Oncogene. 1996; 13 813-822
73 Inada T, Iwama A, Sakano S, Ohno M, Sawada K, Suda T. Selective expression of the receptor tyrosine kinase, HTK, on human erythroid progenitor cells. Blood. 1997; 89 2757-2765
74 Reedquist K A, Ross E, Koop E A et al.. The small GTPase, Rap1, mediates CD31-induced integrin adhesion. J Cell Biol. 2000; 148 1151-1158
75 Katagiri K, Hattori M, Minato N, Irie S, Takatsu K, Kinashi T. Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol Cell Biol. 2000; 20 1956-1969
76 Bertoni A, Tadokoro S, Eto K et al.. Relationships between Rap1b, affinity modulation of integrin alphaIIbbeta3, and the actin cytoskeleton. J Biol Chem. 2002; 277 25715-25721
77 Eto K, Murphy R, Kerrigan S W et al.. Megakaryocytes derived from embryonic stem cells implicate CalDAG-GEFI in integrin signaling. Proc Natl Acad Sci USA. 2002; 99 12819-12824
78 Franke B, Akkerman J WN, Bos J L. Rapid Ca2+-mediated activation of Rap1 in human platelets. EMBO J. 1997; 16 252-259
79 Woulfe D, Jiang H, Mortensen R, Yang J, Brass L F. Activation of Rap1B by Gi family members in platelets. J Biol Chem. 2002; 277 23382-23390
80 De Rooij J, Boenink N M, Van Triest M, Cool R H, Wittinghofer A, Bos J L. PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and Rap2. J Biol Chem. 1999; 274 38125-38130
81 Melaragno M G, Fridell Y- W, Berk B C. The Gas6/Axl system: a novel regulator of vascular cell function. Trends Cardiovasc Med. 1999; 9 250-253
82 Ishimoto Y, Nakano T. Release of a product of growth arrest-specific gene 6 from rat platelets. FEBS Lett. 2000; 466 197-199
83 Angelillo-Scherrer A, De Frutos P G, Aparicio C et al.. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med. 2001; 7 215-221
84 Stitt T N, Conn G, Gore M et al.. The anticoagulation factor protein and its relative, Gas6, are ligands for the Tyro3/Axl family of receptor tyrosine kinases. Cell. 1995; 80 661-670
85 Varnum B C, Young C, Elliott G et al.. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by the growth-arrest-specific gene 6. Nature. 1995; 373 623-626
86 Angelillo-Scherrer A, Charvier S, Plaisance S et al.. Deficiency in one Gas6 receptor (Axl, Sky or Mer) protects mice against thrombosis because of a platelet dysfunction. J Thromb Haemost. 2003; 1(suppl 1) OC245
87 Jurasz P, Chung A W, Radomski A, Radomski M W. Nonremodeling properties of matrix metalloproteinases: the platelet connection. Circ Res. 2002; 90 1041-1043
88 Henn V, Slupsky J R, Gräfe M et al.. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391 591-594
89 Henn V, Steinbach S, Buchner K, Presek P, Kroczek R A. The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood. 2001; 98 1047-1054
90 Hermann A, Rauch B H, Braun M, Schror K, Weber A A. Platelet CD40 ligand (CD40L)-subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets. 2001; 12 74-82
91 Locksley R M, Killeen N, Lenardo M J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001; 104 487-501
92 Andre P, Prasad K S, Denis C V et al.. CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat Med. 2002; 8 247-252
93 Inwald D P, McDowall A, Peters M J, Callard R E, Klein N J. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ Res. 2003; 92 1041-1048
94 Mach F, Schonbeck U, Sukhova G K, Akinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature. 1998; 394 200-203
95 May A E, Kalsch T, Massberg S, Herouy Y, Schmidt R, Gawaz M. Engagement of glycoprotein IIb/IIIa on platelets upregulates CD40L abd triggers CD40L-dependent matrix degradation by endothelial cells. Circulation. 2002; 106 2111-2117
96 Crow A R, Leytin V, Starkey A F, Rand M L, Lazarus A H. CD154 (CD40 ligand)-deficient mice exhibit prolonged bleeding time and decreased shear-induced platelet aggregates. J Thromb Haemost. 2003; 1 850-852
97 MacEwan D J. TNF receptor subtype signaling: differences and cellular consequences. Cell Signal. 2002; 14 477-492
98 Inwald D P, Peters M J, Walshe D, Jones A, Davies E G, Klein N J. Absence of platelet CD40L identifies patients with X-linked hyper IgM syndrome. Clin Exp Immunol. 2000; 120 499-502
99 Prasad K S, Andre P, He M, Bao M, Manganello J, Phillips D R. Soluble CD40 ligand induces {beta}3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA. 2003; 100 12367-12371
100 Heeschen C, Dimmeler S, Hamm C W et al.. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med. 2003; 348 1104-1111
101 Anand S X, Viles-Gonzalez J F, Badimon J J, Cavusoglu E, Marmur J D. Membrane-associated CD40L and sCD40L in atherothrombotic disease. Thromb Haemost. 2003; 90 377-384
102 Cha J K, Jeong M H, Jang J Y et al.. Serial measurement of surface expressions of CD63, P-selectin and CD40 ligand on platelets in atherosclerotic ischemic stroke. A possible role of CD40 ligand on platelets in atherosclerotic ischemic stroke. Cerebrovasc Dis. 2003; 16 376-382
103 Elhabazi A, Delaire S, Bensussan A, Boumsell L, Bismuth G. Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis. J Immunol. 2001; 166 4341-4347
104 Kumanogoh A, Watanabe C, Lee I et al.. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity. 2000; 13 621-631
105 Ishida I, Kumanogoh A, Suzuki K, Akahani S, Noda K, Kikutani H. Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. Int Immunol. 2003; 15 1027-1034
106 Delaire S, Billard C, Tordjman R et al.. Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. J Immunol. 2001; 166 4348-4354
107 Wang X, Kumanogoh A, Watanabe C, Shi W, Yoshida K, Kikutani H. Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses. Blood. 2001; 97 3498-3504
108 Shi W, Kumanogoh A, Watanabe C et al.. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity. 2000; 13 633-642
109 Tamagnone L, Artigiani S, Chen H et al.. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell. 1999; 99 71-80
110 Nakayama E, von Hoegen I, Parnes J R. Sequence of the Lyb-2 B-cell differentiation antigen defines a gene superfamily of receptors with inverted membrane orientation. Proc Natl Acad Sci USA. 1989; 86 1352-1356
111 Ying H, Nakayama E, Robinson W H, Parnes J R. Structure of the mouse CD72 (Lyb-2) gene and its alternatively spliced transcripts. J Immunol. 1995; 154 2743-2752
112 Adachi T, Flaswinkel H, Yakura H, Reth M, Tsubata T. The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J Immunol. 1998; 160 4662-4665
113 Tamagnone L, Comoglio P M. Signaling by semaphorin receptors: cell guidance and beyond. Trends Cell Biol. 2000; 10 377-383
114 Zhu L, Prevost N, Lee V et al.. Semaphorin 4D (CD100) is expressed on the surface of human platelets and proteolytically shed during platelet activation. Blood. 2003; 102 292a
115 Li R Y, Ragab A, Gaits F, Ragab-Thomas J M, Chap H. Thrombin-induced redistribution of protein-tyrosine-phosphatases to the cytoskeletal complexes in human platelets. Cell Mol Biol. 1994; 40 665-675
116 Li R Y, Gaits F, Ragab A, Ragab-Thomas J MF, Chap H. Tyrosine phosphorylation of an SH2-containing protein tyrosine phosphatase is coupled to platelet thrombin receptor via a pertussis toxin-sensitive heterotrimeric G-protein. EMBO J. 1995; 14 2519-2526

Lawrence BrassM.D. Ph.D.

University of Pennsylvania, Room 915 BRB-II

421 Curie Blvd.

Philadelphia, PA 19104

eMail: Brass@mail.med.upenn.edu