Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Anil Chalisey
  • Thomas Hiron
  • Angharad E. Fenton-May
  • Christopher A. O’CallaghanEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_570


Historical Background

CLEC-2 is a 32 kDa C-type lectin-like immune receptor (Colonna et al. 2000; O’Callaghan 2009). CLEC-2 (gene name CLEC1B) is part of the NK (natural killer) gene cluster found on human chromosome 12 and mouse chromosome 6. Within this cluster, CLEC-2 is part of the Dectin-1 subfamily which consists of all type 2 transmembrane proteins with extracellular C-type lectin-like domains (CTLDs) and immune or homeostatic roles. Other members of this cluster include:  CLEC-1,  Dectin-1, CLEC8A (Lox-1), CLEC9A, CLEC12A, and CLEC12B.

CLEC-2 is a type 2 transmembrane signaling protein with its N-terminal region within the cell and its C-terminal region outside the cell. CLEC-2 has a short cytoplasmic region containing a single YxxL motif followed by a single pass transmembrane domain and then an extracellular...
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  1. Abtahian F, Guerriero A, Sebzda E, Lu MM, Zhou R, Mocsai A, et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science. 2003;299(5604):247–51.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Acton SE, Astarita JL, Malhotra D, Lukacs-Kornek V, Franz B, Hess PR, et al. Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity. 2012;37(2):276–89.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Acton SE, Farrugia AJ, Astarita JL, Mourão-Sá D, Jenkins RP, Nye E, et al. Dendritic cells control fibroblastic reticular network tension and lymph node expansion. Nature. 2014;514(7523):498–502.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bénézech C, Nayar S, Finney BA, Withers DR, Lowe K, Desanti GE. CLEC-2 is required for development and maintenance of lymph nodes. Blood. 2014;123(20):3200–7.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bertozzi CC, Schmaier AA, Mericko P, Hess PR, Zou Z, Chen M, et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood. 2010;116(4):661–70.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Chaipan C, Soilleux EJ, Simpson P, Hofmann H, Gramberg T, Marzi A, et al. DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. J Virol. 2006;80(18):8951–60.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Chaipan C, Steffen I, Tsegaye TS, Bertram S, Glowacka I, Kato Y, et al. Incorporation of podoplanin into HIV released from HEK-293T cells, but not PBMC, is required for efficient binding to the attachment factor CLEC-2. Retrovirology. 2010;7:47.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Christou CM, Pearce AC, Watson AA, Mistry AR, Pollitt AY, Fenton-May AE, et al. Renal cells activate the platelet receptor CLEC-2 through podoplanin. Biochem J. 2008;411(1):133–40.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Colonna M, Samaridis J, Angman L. Molecular characterization of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells. Eur J Immunol. 2000;30(2):697–704.PubMedCrossRefGoogle Scholar
  10. Cueni LN, Chen L, Zhang H, Marino D, Huggenberger R, Alitalo A, 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(20):4376–84.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Finney BA, Schweighoffer E, Navarro-Núñez L, Bénézech C, Barone F, Hughes CE, et al. CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood. 2012;119(7):1747–56.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Fuller GL, Williams JA, Tomlinson MG, Eble JA, Hanna SL, Pohlmann S, 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(17):12397–409.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Hatakeyama K, Kaneko MK, Kato Y, Ishikawa T, Nishihira K, Tsujimoto Y, et al. Podoplanin expression in advanced atherosclerotic lesions of human aortas. Thromb Res. 2012;129(4):e70–6.PubMedCrossRefGoogle Scholar
  14. Hooley E, Papagrigoriou E, Navdaev A, Pandey AV, Clemetson JM, Clemetson KJ, et al. The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure. Biochemistry. 2008;47(30):7831–7.PubMedCrossRefGoogle Scholar
  15. Hughes CE, Navarro-Nunez L, Finney BA, Mourao-Sa D, Pollitt AY, Watson SP. CLEC-2 is not required for platelet aggregation at arteriolar shear. J Thromb Haemost. 2010a;8(10):2328–32.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Hughes CE, Pollitt AY, Mori J, Eble JA, Tomlinson MG, Hartwig JH, et al. CLEC-2 activates Syk through dimerization. Blood. 2010b;115(14):2947–55.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Hughes CE, Sinha U, Pandey A, Eble JA, O'Callaghan CA, Watson SP. 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):5127–35.PubMedCrossRefGoogle Scholar
  18. Ichise H, Ichise T, Ohtani O, Yoshida N. Phospholipase Cgamma2 is necessary for separation of blood and lymphatic vasculature in mice. Development. 2009;136(2):191–5.PubMedCrossRefGoogle Scholar
  19. Kerrigan AM, Navarro-Nuñez L, Pyz E, Finney BA, Willment JA, Watson SP, Brown GD. Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. J Thromb Haemost. 2012;10(3):484–6.PubMedPubMedCentralCrossRefGoogle Scholar
  20. May F, Hagedorn I, Pleines I, Bender M, Vogtle T, Eble J, et al. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood. 2009;114(16):3464–72.PubMedCrossRefGoogle Scholar
  21. Nagae M, Morita-Matsumoto K, Kato M, Kaneko MK, Kato Y, Yamaguchi Y. A platform of C-type lectin-like receptor CLEC-2 for binding O-glycosylated podoplanin and nonglycosylated rhodocytin. Structure. 2014;22(12):1711–21.PubMedCrossRefGoogle Scholar
  22. O’Callaghan CA. Thrombomodulation via CLEC-2 targeting. Curr Opin Pharmacol. 2009;9(2):90–5.PubMedCrossRefGoogle Scholar
  23. Pollitt AY, Grygielska B, Leblond B, Desire L, Eble JA, Watson SP. Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization, secondary mediators, and Rac. Blood. 2010;115(14):2938–46.PubMedCrossRefGoogle Scholar
  24. Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 2003;22(14):3546–56.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Suzuki-Inoue K, Fuller GL, Garcia A, Eble JA, Pohlmann S, Inoue O, et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood. 2006;107(2):542–9.PubMedCrossRefGoogle Scholar
  26. Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem. 2007;282(36):25993–6001.PubMedCrossRefGoogle Scholar
  27. Suzuki-Inoue K, Inoue O, Ding G, Nishimura S, Hokamura K, Eto K, et al. Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem. 2010;285(32):24494–507.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Tang T, Li L, Tang J, Li Y, Lin WY, Martin F, et al. A mouse knockout library for secreted and transmembrane proteins. Nat Biotechnol. 2010;28(7):749–55.PubMedCrossRefGoogle Scholar
  29. Watanabe M, Sugimoto Y, Tsuruo T. Expression of a Mr 41,000 glycoprotein associated with thrombin-independent platelet aggregation in high metastatic variants of murine B16 melanoma. Cancer Res. 1990;50(20):6657–62.PubMedPubMedCentralGoogle Scholar
  30. Watson AA, O’Callaghan CA. Crystallization and X-ray diffraction analysis of human CLEC-2. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005;61(Pt 12):1094–6.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Watson AA, Brown J, Harlos K, Eble JA, Walter TS, O’Callaghan CA. The crystal structure and mutational binding analysis of the extracellular domain of the platelet-activating receptor CLEC-2. J Biol Chem. 2007;282(5):3165–72.PubMedCrossRefGoogle Scholar
  32. Watson AA, Christou CM, James JR, Fenton-May AE, Moncayo GE, Mistry AR, et al. The platelet receptor CLEC-2 is active as a dimer. Biochemistry. 2009;48(46):10988–96.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Anil Chalisey
    • 1
  • Thomas Hiron
    • 1
  • Angharad E. Fenton-May
    • 1
  • Christopher A. O’Callaghan
    • 1
    Email author
  1. 1.Centre for Cellular and Molecular Physiology, Nuffield Department of Clinical MedicineUniversity of OxfordHeadingtonUK