The physiological and pathophysiological roles of platelet CLEC-2

 

 Buy Article Permissions and Reprints

Summary

CLEC-2 is a C-type lectin receptor which is highly expressed on platelets but also found at low levels on different immune cells. CLEC-2 elicits powerful platelet activation upon engagement by its endogenous ligand, the mucin-type glycoprotein podoplanin. Podoplanin is expressed in a variety of tissues, including lymphatic endothelial cells, kidney podocytes, type I lung epithelial cells, lymph node stromal cells and the choroid plexus epithelium. Animal models have shown that the correct separation of the lymphatic and blood vasculatures during embryonic development is dependent on CLEC-2-mediated platelet activation. Additionally, podoplanin-deficient mice show abnormalities in heart, lungs, and lymphoid tissues, whereas absence of CLEC-2 affects brain development. This review summarises the current understanding of the molecular pathways regulating CLEC-2 and podoplanin function and suggests other physiological and pathological processes where this molecular interaction might exert crucial roles.

• References

• 1 George JN. Platelets. Lancet 2000; 355: 1531-1539.
  CrossrefPubMedGoogle Scholar
• 2 Levin J. The evolution of mammalian platelets. Platelets. 2nd Edition. Academic Press; 2007: 3-22.
  Google Scholar
• 3 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
  CrossrefPubMedGoogle Scholar
• 4 Nachman RL, Rafii S. Platelets, petechiae, and preservation of the vascular wall. N Engl J Med 2008; 359: 1261-1270.
  CrossrefPubMedGoogle Scholar
• 5 Anitua E, Andia I, Ardanza B. et al. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost 2004; 91: 4-15.
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost 2011; 105 (Suppl. 01) S13-S33.
  Article in Thieme ConnectPubMedGoogle Scholar
• 7 Echtler K, Stark K, Lorenz M. et al. Platelets contribute to postnatal occlusion of the ductus arteriosus. Nat Med 2009; 16: 75-82.
  PubMedGoogle Scholar
• 8 Bertozzi CC, Schmaier AA, Mericko P. et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 2010; 116: 661-670.
  CrossrefPubMedGoogle Scholar
• 9 Carramolino L, Fuentes J, García-Andrés C. et al. Platelets Play an Essential Role in Separating the Blood and Lymphatic Vasculatures During Embryonic Angiogenesis. Circ Res 2010; 106: 1197-1201.
  CrossrefPubMedGoogle Scholar
• 10 Finney BA, Schweighoffer E, Navarro-Nuñez L. et al. CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood 2012; 119: 1747-1756.
  CrossrefPubMedGoogle Scholar
• 11 Suzuki-Inoue K, Inoue O, Ding G. et al. Essential in Vivo Roles of the C-type Lectin Receptor CLEC-2. J Biol Chem 2010; 285: 24494-24507.
  CrossrefPubMedGoogle Scholar
• 12 Alitalo K. The lymphatic vasculature in disease. Nat Med 2011; 17: 1371-1380.
  CrossrefPubMedGoogle Scholar
• 13 Schacht V, Ramirez MI, Hong YK. et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 2003; 22: 3546-3556.
  CrossrefPubMedGoogle Scholar
• 14 Uhrin P, Zaujec J, Breuss JM. et al. Novel function for blood platelets and podo-planin in developmental separation of blood and lymphatic circulation. Blood 2010; 115: 3997-4005.
  CrossrefPubMedGoogle Scholar
• 15 Fu J, Gerhardt H, McDaniel JM. et al. Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest 2008; 118: 3725-3737.
  CrossrefPubMedGoogle Scholar
• 16 Abtahian F, Guerriero A, Sebzda E. et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 2003; 299: 247-251.
  CrossrefPubMedGoogle Scholar
• 17 Bohmer R, Neuhaus B, Buhren S. et al. Regulation of developmental lymphan-giogenesis by Syk(+) leukocytes. Dev Cell 2010; 18: 437-449.
  CrossrefPubMedGoogle Scholar
• 18 Ichise H, Ichise T, Ohtani O. et al. Phospholipase C gamma2 is necessary for separation of blood and lymphatic vasculature in mice. Development 2009; 136: 191-195.
  CrossrefPubMedGoogle Scholar
• 19 Suzuki-Inoue K, Fuller GL, García A. et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 2006; 107: 542-549.
  CrossrefPubMedGoogle Scholar
• 20 Suzuki-Inoue K, Kato Y, Inoue O. et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 2007; 282: 25993-26001.
  CrossrefPubMedGoogle Scholar
• 21 Mourão-SÃ D, Robinson MJ, Zelenay S. et al. CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses. Eur J Immunol 2011; 41: 3040-3053.
  CrossrefPubMedGoogle Scholar
• 22 Huysamen C, Brown GD. The fungal pattern recognition receptor, Dectin-1, and the associated cluster of C-type lectin-like receptors. FEMS Microbiol Lett 2009; 290: 121-128.
  PubMedGoogle Scholar
• 23 Colonna M, Samaridis J, Angman L. Molecular characterisation of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells. Eur J Immunol 2000; 30: 697-704.
  CrossrefPubMedGoogle Scholar
• 24 Fuller GL, Williams JA, Tomlinson MG. et al. The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade. J Biol Chem 2007; 282: 12397-12409.
  CrossrefPubMedGoogle Scholar
• 25 Hughes CE, Pollitt AY, Mori J. et al. CLEC-2 activates Syk through dimerisation. Blood 2010; 115: 2947-2955.
  CrossrefPubMedGoogle Scholar
• 26 Séverin S, Pollitt AY, Navarro-Nuñez L. et al. Syk-dependent Phosphorylation of CLEC-2. J Biol Chem 2011; 286: 4107-4116.
  CrossrefPubMedGoogle Scholar
• 27 Parguiña AF, Alonso J, Rosa I. et al. A detailed proteomic analysis of rhodocy-tin-activated platelets reveals novel clues on the CLEC-2 signalosome: implications for CLEC-2 signaling regulation. Blood 2012; 120: e117-e126.
  CrossrefPubMedGoogle Scholar
• 28 Pollitt AY, Grygielska B, Leblond B. et al. Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerisation, secondary mediators, and Rac. Blood 2010; 115: 2938-2946.
  CrossrefPubMedGoogle Scholar
• 29 May F, Hagedorn I, Pleines I. et al. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 2009; 114: 3464-3472.
  CrossrefPubMedGoogle Scholar
• 30 Bender M, May F, Lorenz V. et al. Combined in vivo depletion of glycoprotein VI and C-type lectin-like receptor 2 severely compromises hemostasis and abrogates arterial thrombosis in mice. Arterioscler Thromb Vasc Biol . 2013 Epub ahead of print
  PubMedGoogle Scholar
• 31 Hughes CE, Navarro-Nuñez L, Finney BA. et al. CLEC-2 is not required for platelet aggregation at arteriolar shear. J Thromb Haemost 2010; 08: 2328-2332.
  CrossrefPubMedGoogle Scholar
• 32 Law DA, Nannizzi-Alaimo L, Ministri K. et al. Genetic and pharmacological analyses of Syk function in alphaIIbbeta3 signaling in platelets. Blood 1999; 93: 2645-2652.
  PubMedGoogle Scholar
• 33 Poole A, Gibbins JM, Turner M. et al. The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen. EMBO J 1997; 16: 2333-2341.
  CrossrefPubMedGoogle Scholar
• 34 Andre P, Morooka T, Sim D. et al. Critical role for Syk in responses to vascular injury. Blood 2011; 118: 5000-5010.
  CrossrefPubMedGoogle Scholar
• 35 Hou TZ, Bystrom J, Sherlock JP. et al. A distinct subset of podoplanin (gp38) expressing F4/80+ macrophages mediate phagocytosis and are induced following zymosan peritonitis. FEBS Lett 2010; 584: 3955-3961.
  CrossrefPubMedGoogle Scholar
• 36 Sawa Y. New trends in the study of podoplanin as a cell morphological regulator. JDSR 2010; 46: 165-172.
  PubMedGoogle Scholar
• 37 Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 2002; 03: 586-599.
  PubMedGoogle Scholar
• 38 Charrin S, Alcover A. Role of ERM (ezrin-radixin-moesin) proteins in T lymphocyte polarisation, immune synapse formation and in T cell receptor-mediated signaling. Front Biosci 2006; 11: 1987-1997.
  CrossrefPubMedGoogle Scholar
• 39 Scholl FG, Gamallo C, Vilaro S. et al. Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein that induces plasma membrane extensions and increased motility in keratinocytes. J Cell Sci 1999; 112: 4601-4613.
  PubMedGoogle Scholar
• 40 Wicki A, Lehembre F, Wick N. et al. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytos-keleton. Cancer Cell 2006; 09: 261-272.
  CrossrefPubMedGoogle Scholar
• 41 Navarro A, Perez RE, Rezaiekhaligh M. et al. T1alpha/podoplanin is essential for capillary morphogenesis in lymphatic endothelial cells. Am J Physiol Lung Cell Mol Physiol 2008; 295: L543-L551.
  CrossrefPubMedGoogle Scholar
• 42 Navarro A, Perez RE, Rezaiekhaligh MH. et al. Polarized migration of lymphatic endothelial cells is critically dependent on podoplanin regulation of Cdc42. Am J Physiol Lung Cell Mol Physiol 2011; 300: L32-L42.
  CrossrefPubMedGoogle Scholar
• 43 Martin-Villar E, Megias D, Castel S. et al. Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J Cell Sci 2006; 119: 4541-4553.
  CrossrefPubMedGoogle Scholar
• 44 Kerosuo L, Bronner-Fraser M. What is bad in cancer is good in the embryo: Importance of EMT in neural crest development. Semin Cell Dev Biol 2012; 23: 320-332.
  CrossrefPubMedGoogle Scholar
• 45 Mahtab EA, Vicente-Steijn R, Hahurij ND. et al. Podoplanin deficient mice show a RhoA-related hypoplasia of the sinus venosus myocardium including the sinoatrial node. Dev Dyn 2009; 238: 183-193.
  CrossrefPubMedGoogle Scholar
• 46 Bertozzi CC, Hess PR, Kahn ML. Platelets: covert regulators of lymphatic development. Arterioscler Thromb Vasc Biol 2010; 30: 2368-2371.
  CrossrefPubMedGoogle Scholar
• 47 Nurden AT, Freson K, Seligsohn U. Inherited platelet disorders. Haemophilia 2012; 18 (Suppl. 04) 154-160.
  CrossrefPubMedGoogle Scholar
• 48 Emambokus NR, Frampton J. The glycoprotein IIb molecule is expressed on early murine hematopoietic progenitors and regulates their numbers in sites of hematopoiesis. Immunity 2003; 19: 33-45.
  CrossrefPubMedGoogle Scholar
• 49 Hodivala-Dilke KM, McHugh KP, Tsakiris DA. et al. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 1999; 103: 229-238.
  CrossrefPubMedGoogle Scholar
• 50 Monkley SJ, Kostourou V, Spence L. et al. Endothelial cell talin1 is essential for embryonic angiogenesis. Dev Biol 2011; 349: 494-502.
  CrossrefPubMedGoogle Scholar
• 51 Bialkowska K, Ma Y-Q, Bledzka K. 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: 18640-18649.
  CrossrefPubMedGoogle Scholar
• 52 Malinin NL, Zhang L, Choi J. et al. A point mutation in kindlin3 ablates activation of three integrin subfamilies in humans. Nat Med 2009; 15: 313-318.
  CrossrefPubMedGoogle Scholar
• 53 Bazigou E, Xie S, Chen C. et al. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 2009; 17: 175-186.
  CrossrefPubMedGoogle Scholar
• 54 Huang XZ, Wu JF, Ferrando R. et al. Fatal Bilateral Chylothorax in Mice Lacking the Integrin α9β1. Mol Cell Biol 2000; 20: 5208-5215.
  CrossrefPubMedGoogle Scholar
• 55 Garmy-Susini B, Avraamides CJ, Schmid MC. et al. Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res 2010; 70: 3042-3051.
  CrossrefPubMedGoogle Scholar
• 56 Martin-Villar E, Fernandez-Munoz B, Parsons M. et al. Podoplanin associates with CD44 to promote directional cell migration. Mol Biol Cell 2010; 21: 4387-4399.
  CrossrefPubMedGoogle Scholar
• 57 Kunita A, Kashima TG, Ohazama A. et al. Podoplanin is regulated by AP-1 and promotes platelet aggregation and cell migration in osteosarcoma. Am J Pathol 2011; 179: 1041-1049.
  CrossrefPubMedGoogle Scholar
• 58 Cueni LN, Chen L, Zhang H. et al. Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin. Blood 2010; 116: 4376-4384.
  CrossrefPubMedGoogle Scholar
• 59 Osada M, Inoue O, Ding G. et al. Platelet activation receptor CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells. J Biol Chem 2012; 287: 22241-22252.
  CrossrefPubMedGoogle Scholar
• 60 Coppinger JA, O’Connor R, Wynne K. et al. Moderation of the platelet releasate response by aspirin. Blood 2007; 109: 4786-4792.
  CrossrefPubMedGoogle Scholar
• 61 Tang T, Li L, Tang J. et al. A mouse knockout library for secreted and transmembrane proteins. Nat Biotechnol 201 (28) 749-755.
  PubMedGoogle Scholar
• 62 Redzic ZB, Preston JE, Duncan JA. et al. The choroid plexus-cerebrospinal fluid system: from development to aging. Curr Top Dev Biol 2005; 71: 1-52.
  PubMedGoogle Scholar
• 63 Reboldi A, Coisne C, Baumjohann D. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 2009; 10: 514-523.
  CrossrefPubMedGoogle Scholar
• 64 Shankland SJ. The podocyte’s response to injury: Role in proteinuria and glome-rulosclerosis. Kidney Int 2006; 69: 2131-2147.
  CrossrefPubMedGoogle Scholar
• 65 Koop K, Eikmans M, Wehland M. et al. Selective loss of podoplanin protein expression accompanies proteinuria and precedes alterations in podocyte morphology in a spontaneous proteinuric rat model. Am J Pathol 2008; 173: 315-326.
  CrossrefPubMedGoogle Scholar
• 66 Matsui K, Breitender-Geleff S, Soleiman A. et al. Podoplanin, a novel 43-kDa membrane protein, controls the shape of podocytes. Nephrol Dial Transplant 1999; 14 (Suppl. 01) 9-11.
  PubMedGoogle Scholar
• 67 Schmieder S, Nagai M, Orlando RA. et al. Podocalyxin activates RhoA and induces actin reorganisation through NHERF1 and Ezrin in MDCK cells. J Am Soc Nephrol 2004; 15: 2289-2298.
  CrossrefPubMedGoogle Scholar
• 68 Millien G, Spira A, Hinds A. et al. Alterations in gene expression in T1 alpha null lung: a model of deficient alveolar sac development. BMC Dev Biol 2006; 06: 35.
  CrossrefPubMedGoogle Scholar
• 69 Ramirez MI, Millien G, Hinds A. et al. T1α, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev Biol 2003; 256: 61-72.
  PubMedGoogle Scholar
• 70 Kerrigan AM, Dennehy KM, Mourão-SÃ D. et al. CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils. J Immunol 2009; 182: 4150-4157.
  CrossrefPubMedGoogle Scholar
• 71 Kerrigan AM, Navarro-Nuñez L, Pyz E. et al. Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. J Thromb Haemost 2012; 10: 484-486.
  CrossrefPubMedGoogle Scholar
• 72 Tal O, Lim HY, Gurevich I. et al. DC mobilisation from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J Exp Med 2011; 208: 2141-2153.
  CrossrefPubMedGoogle Scholar
• 73 Acton SE, Astarita JL, Malhotra D. et al. Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 2012; 37: 276-289.
  CrossrefPubMedGoogle Scholar
• 74 van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol 2010; 10: 664-674.
  CrossrefPubMedGoogle Scholar
• 75 Peters A, Pitcher LA, Sullivan JM. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 2011; 35: 986-996.
  CrossrefPubMedGoogle Scholar
• 76 Miyamoto Y, Uga H, Tanaka S. et al. Podoplanin is an inflammatory protein up-regulated in Th17 cells in SKG arthritic joints. Mol Immunol 2012; 54: 199-207.
  PubMedGoogle Scholar
• 77 Ekwall AK, Eisler T, Anderberg C. et al. The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis. Arthritis Res Ther 2011; 13: R40.
  CrossrefPubMedGoogle Scholar
• 78 Boulaftali Y, Hess PR, Getz TM. et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest . 2013 Epub ahead of print
  PubMedGoogle Scholar
• 79 Kato K, Kanaji T, Russell S. et al. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion. Blood 2003; 102: 1701-1707.
  CrossrefPubMedGoogle Scholar
• 80 Lockyer S, Okuyama K, Begum S. et al. GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary throm-boembolism. Thromb Res 2006; 118: 371-380.
  CrossrefPubMedGoogle Scholar
• 81 Alexander JS, Ganta VC, Jordan PA. et al. Gastrointestinal lymphatics in health and disease. Pathophysiology 2010; 17: 315-335.
  CrossrefPubMedGoogle Scholar
• 82 Lowe KL, Navarro-Nuñez L, Watson SP. Platelet CLEC-2 and podoplanin in cancer metastasis. Throm Res 2012; 129 (Suppl. 01) S30-S37.
  PubMedGoogle Scholar
• 83 Erpenbeck L, Schon MP. Deadly allies: the fatal interplay between platelets and metastasising cancer cells. Blood 2010; 115: 3427-3436.
  CrossrefPubMedGoogle Scholar
• 84 Cueni LN, Hegyi I, Shin JW. et al. Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. Am J Pathol 2010; 177: 1004-1016.
  CrossrefPubMedGoogle Scholar
• 85 Martin-Villar E, Scholl FG, Gamallo C. et al. Characterisation of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int J Cancer 2005; 113: 899-910.
  CrossrefPubMedGoogle Scholar
• 86 Schacht V, Dadras SS, Johnson LA. et al. Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol 2005; 166: 913-921.
  CrossrefPubMedGoogle Scholar
• 87 Kunita A, Kashima TG, Morishita Y. et al. The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis. Am J Pathol 2007; 170: 1337-1347.
  CrossrefPubMedGoogle Scholar
• 88 Kato Y, Kaneko MK, Kunita A. et al. Molecular analysis of the pathophysiologi-cal binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2. Cancer Sci 2008; 99: 54-61.
  PubMedGoogle Scholar
• 89 Nakazawa Y, Takagi S, Sato S. et al. Prevention of hematogenous metastasis by neutralising mice and its chimeric anti-Aggrus/podoplanin antibodies. Cancer Sci 2011; 102: 2051-2057.
  CrossrefPubMedGoogle Scholar
• 90 Hatakeyama K, Kaneko MK, Kato Y. et al. Podoplanin expression in advanced atherosclerotic lesions of human aortas. Thromb Res 2012; 129: e70-e76.
  CrossrefPubMedGoogle Scholar