Semin Thromb Hemost 2004; 30(4): 399-410
DOI: 10.1055/s-2004-833475
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

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
Further Information

Publication History

Publication Date:
08 September 2004 (online)

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.

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

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Email: Brass@mail.med.upenn.edu