Advertisement

International Journal of Hematology

, Volume 110, Issue 3, pp 285–294 | Cite as

Soluble CLEC-2 is generated independently of ADAM10 and is increased in plasma in acute coronary syndrome: comparison with soluble GPVI

  • Osamu Inoue
  • Makoto Osada
  • Junya Nakamura
  • Fuminori Kazama
  • Toshiaki Shirai
  • Nagaharu Tsukiji
  • Tomoyuki Sasaki
  • Hiroshi Yokomichi
  • Tomotaka Dohi
  • Makoto Kaneko
  • Makoto Kurano
  • Mitsuru Oosawa
  • Shogo Tamura
  • Kaneo Satoh
  • Katsuhiro Takano
  • Katsumi Miyauchi
  • Hiroyuki Daida
  • Yutaka Yatomi
  • Yukio Ozaki
  • Katsue Suzuki-InoueEmail author
Original Article
  • 156 Downloads

Abstract

Soluble forms of platelet membrane proteins are released upon platelet activation. We previously reported that soluble C-type lectin-like receptor 2 (sCLEC-2) is released as a shed fragment (Shed CLEC-2) or as a whole molecule associated with platelet microparticles (MP-CLEC-2). In contrast, soluble glycoprotein VI (sGPVI) is released as a shed fragment (Shed GPVI), but not as a microparticle-associated form (MP-GPVI). However, mechanism of sCLEC-2 generation or plasma sCLEC-2 has not been fully elucidated. Experiments using metalloproteinase inhibitors/stimulators revealed that ADAM10/17 induce GPVI shedding, but not CLEC-2 shedding, and that shed CLEC-2 was partially generated by MMP-2. Although MP-GPVI was not generated, it was generated in the presence of the ADAM10 inhibitor. Moreover, antibodies against the cytoplasmic or extracellular domain of GPVI revealed the presence of the GPVI cytoplasmic domain, but not the extracellular domain, in the microparticles. These findings suggest that most of the GPVI on microparticles are induced to shed by ADAM10; MP-GPVI is thus undetected. Plasma sCLEC-2 level was 1/32 of plasma sGPVI level in normal subjects, but both soluble proteins significantly increased in plasma of patients with acute coronary syndrome. Thus, sCLEC-2 and sGPVI are released by different mechanisms and released in vivo upon platelet activation.

Keywords

Platelets Soluble CLEC-2 Soluble GPVI ADAM10 Biomarker 

Notes

Acknowledgements

We thank Hideyuki Tanaka, Chiaki Komatsu, and Hisaichiro Nakazawa for their help of the study. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (M.O.) and the Japan Society for the Promotion of Science (JSPS) through the Funding Program for Next Generation World-leading Researchers (NEXT Program, LS-052) (K.S-I.).

Compliance with ethical standards

Conflict of interest

Junya Nakamura and Mitsuru Oosawa are an ex-employee and an employee of LSI Medicine Corporation, respectively. Yukio Ozaki, Katsue Suzuki-Inoue, Junya Nakamura, and Mitsuru Oosawa have a patent related to this report (patent no. 6078845) in Japan.

Supplementary material

12185_2019_2680_MOESM1_ESM.jpg (1.2 mb)
Supplementary material 1 (JPEG 1257 kb)
12185_2019_2680_MOESM2_ESM.jpg (1.6 mb)
Supplementary material 2 (JPEG 1622 kb)
12185_2019_2680_MOESM3_ESM.jpg (1.7 mb)
Supplementary material 3 (JPEG 1738 kb)

References

  1. 1.
    Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor? Blood. 2003;102:449–61.CrossRefPubMedGoogle Scholar
  2. 2.
    Gurney D, Lip GY, Blann AD. A reliable plasma marker of platelet activation: does it exist? Am J Hematol. 2002;70:139–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Nomura S. Extracellular vesicles and blood diseases. Int J Hematol. 2017;105:392–405.CrossRefPubMedGoogle Scholar
  4. 4.
    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;107:542–9.CrossRefGoogle Scholar
  5. 5.
    Suzuki-Inoue K, Osada M, Ozaki Y. Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood. J Thromb Haemost. 2017;15:219–29.CrossRefGoogle Scholar
  6. 6.
    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;282:25993–6001.CrossRefGoogle Scholar
  7. 7.
    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;411:133–40.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tsuruo T, Fujita N. Platelet aggregation in the formation of tumor metastasis. Proc Jpn Acad Ser B Phys Biol Sci. 2008;84:189–98.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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;116:661–70.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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;285:24494–507.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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;80:8951–60.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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;28:749–55.CrossRefPubMedGoogle Scholar
  13. 13.
    Gitz E, Pollitt AY, Gitz-Francois JJ, Alshehri O, Mori J, Montague S, et al. CLEC-2 expression is maintained on activated platelets and on platelet microparticles. Blood. 2014;124:2262–70.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kazama F, Nakamura J, Osada M, Inoue O, Oosawa M, Tamura S, et al. Measurement of soluble C-type lectin-like receptor 2 in human plasma. Platelets. 2015;26:711–9.CrossRefGoogle Scholar
  15. 15.
    Aota T, Naitoh K, Wada H, Yamashita Y, Miyamoto N, Hasegawa M, et al. Elevated soluble platelet glycoprotein VI is a useful marker for DVT in postoperative patients treated with edoxaban. Int J Hematol. 2014;100:450–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Inoue O, Suzuki-Inoue K, Shinoda D, Umeda Y, Uchino M, Takasaki S, et al. Novel synthetic collagen fibers, poly(PHG), stimulate platelet aggregation through glycoprotein VI. FEBS Lett. 2009;583:81–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Osada M, Inoue O, Ding G, Shirai T, Ichise H, Hirayama K, 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;287:22241–52.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dohi T, Miyauchi K, Ohkawa R, Nakamura K, Kishimoto T, Miyazaki T, et al. Increased circulating plasma lysophosphatidic acid in patients with acute coronary syndrome. Clin Chim Acta. 2012;413:207–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.CrossRefGoogle Scholar
  20. 20.
    Gardiner EE, Karunakaran D, Shen Y, Arthur JF, Andrews RK, Berndt MC. Controlled shedding of platelet glycoprotein (GP)VI and GPIb-IX-V by ADAM family metalloproteinases. J Thromb Haemost. 2007;5:1530–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Al-Tamimi M, Tan CW, Qiao J, Pennings GJ, Javadzadegan A, Yong AS, et al. Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. Blood. 2012;119:4311–20.CrossRefPubMedGoogle Scholar
  22. 22.
    Ezumi Y, Shindoh K, Tsuji M, Takayama H. Physical and functional association of the Src family kinases Fyn and Lyn with the collagen receptor glycoprotein VI-Fc receptor gamma chain complex on human platelets. J Exp Med. 1998;188:267–76.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wijeyewickrema LC, Gardiner EE, Moroi M, Berndt MC, Andrews RK. Snake venom metalloproteinases, crotarhagin and alborhagin, induce ectodomain shedding of the platelet collagen receptor, glycoprotein VI. Thromb Haemost. 2007;98:1285–90.CrossRefPubMedGoogle Scholar
  24. 24.
    Bender M, Hofmann S, Stegner D, Chalaris A, Bosl M, Braun A, et al. Differentially regulated GPVI ectodomain shedding by multiple platelet-expressed proteinases. Blood. 2010;116:3347–55.CrossRefPubMedGoogle Scholar
  25. 25.
    Reinboldt S, Wenzel F, Rauch BH, Hohlfeld T, Grandoch M, Fischer JW, et al. Preliminary evidence for a matrix metalloproteinase-2 (MMP-2)-dependent shedding of soluble CD40 ligand (sCD40L) from activated platelets. Platelets. 2009;20:441–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Naitoh K, Hosaka Y, Honda M, Ogawa K, Shirakawa K, Furusako S. Properties of soluble glycoprotein VI, a potential platelet activation biomarker. Platelets. 2015;26:745–50.CrossRefPubMedGoogle Scholar
  27. 27.
    Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest. 2019;129:12–23.CrossRefPubMedGoogle Scholar
  28. 28.
    Seizer P, May AE. Platelets and matrix metalloproteinases. Thromb Haemost. 2013;110:903–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Al-Tamimi M, Mu FT, Moroi M, Gardiner EE, Berndt MC, Andrews RK. Measuring soluble platelet glycoprotein VI in human plasma by ELISA. Platelets. 2009;20:143–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Herzog BH, Fu J, Wilson SJ, Hess PR, Sen A, McDaniel JM, et al. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature. 2013;502:105–9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Miyasaka M, Tanaka T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol. 2004;4:360.CrossRefPubMedGoogle Scholar
  32. 32.
    Inoue O, Suzuki-Inoue K, McCarty OJ, Moroi M, Ruggeri ZM, Kunicki TJ, et al. Laminin stimulates spreading of platelets through integrin alpha6beta1-dependent activation of GPVI. Blood. 2006;107:1405–12.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Bigalke B, Potz O, Kremmer E, Geisler T, Seizer P, Puntmann VO, et al. Sandwich immunoassay for soluble glycoprotein VI in patients with symptomatic coronary artery disease. Clin Chem. 2011;57:898–904.CrossRefPubMedGoogle Scholar
  34. 34.
    Onselaer MB, Hardy AT, Wilson C, Sanchez X, Babar AK, Miller JLC, et al. Fibrin and D-dimer bind to monomeric GPVI. Blood Adv. 2017;1:1495–504.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Facey A, Pinar I, Arthur JF, Qiao J, Jing J, Mado B, et al. A-disintegrin and metalloproteinase (adam) 10 activity on resting and activated platelets. Biochemistry. 2016;55:1187–94.CrossRefPubMedGoogle Scholar
  36. 36.
    Al-Tamimi M, Arthur JF, Gardiner E, Andrews RK. Focusing on plasma glycoprotein VI. Thromb Haemost. 2012;107:648–55.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang X, Zhang W, Wu X, Li H, Zhang C, Huang Z, et al. Prognostic significance of plasma CLEC-2 (C-type lectin-like receptor 2) in patients with acute ischemic stroke. Stroke. 2018.  https://doi.org/10.1161/STROKEAHA.118.022563.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Osamu Inoue
    • 1
  • Makoto Osada
    • 2
    • 3
  • Junya Nakamura
    • 4
  • Fuminori Kazama
    • 2
  • Toshiaki Shirai
    • 2
  • Nagaharu Tsukiji
    • 2
  • Tomoyuki Sasaki
    • 2
  • Hiroshi Yokomichi
    • 5
  • Tomotaka Dohi
    • 6
  • Makoto Kaneko
    • 7
  • Makoto Kurano
    • 7
  • Mitsuru Oosawa
    • 4
  • Shogo Tamura
    • 2
    • 8
  • Kaneo Satoh
    • 2
  • Katsuhiro Takano
    • 2
  • Katsumi Miyauchi
    • 6
  • Hiroyuki Daida
    • 6
  • Yutaka Yatomi
    • 7
  • Yukio Ozaki
    • 9
  • Katsue Suzuki-Inoue
    • 2
    Email author
  1. 1.Infection Control Office, University of Yamanashi Hospital, Faculty of MedicineUniversity of YamanashiYamanashiJapan
  2. 2.Department of Clinical and Laboratory Medicine, Faculty of MedicineUniversity of YamanashiYamanashiJapan
  3. 3.Graduate School of Health ScienceGunma Paz UniversityGunmaJapan
  4. 4.Department of Antibody Group, Narita R&D Department, Research and Development DivisionLSI Medience CorporationChibaJapan
  5. 5.Department of Health Sciences, Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiYamanashiJapan
  6. 6.Department of Cardiovascular MedicineJuntendo University School of MedicineTokyoJapan
  7. 7.Department of Laboratory Medicine, Graduate School of MedicineUniversity of TokyoTokyoJapan
  8. 8.Japan Society for the Promotion of ScienceTokyoJapan
  9. 9.Fuefuki Chuo HospitalYamanashiJapan

Personalised recommendations