OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press31010.17650/1818-8346-2018-13-3-83-90BASIC RESEARCHФУНДАМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ В ПРАКТИЧЕСКОЙ МЕДИЦИНЕ НА СОВРЕМЕННОМ ЭТАПЕPhysiological and pathophysiological aspects of blood platelet activation through CLEC-2 receptorФизиологические и патофизиологические аспекты активации тромбоцитов крови через рецептор CLEC-2https://orcid.org/0000-0003-0211-6325MartyanovA. A.МартьяновА. А.
Russian Federation

1 Samory Mashela St., Moscow 117198.

1, bldg. 2 Leninskie Gory, Moscow 119991.

4 Kosygina St., Moscow 119991.

117997 Москва, ул. Саморы Машела, 1.

119991 Москва, Ленинские горы, 1, стр. 2.

119991 Москва, ул. Косыгина, 4.

 

KanevaV. N.КаневаВ. Н.
Russian Federation

1 Samory Mashela St., Moscow 117198.

1, bldg. 2 Leninskie Gory, Moscow 119991.

117997 Москва, ул. Саморы Машела, 1.

119991 Москва, Ленинские горы, 1, стр. 2.

PanteleevM. A.ПантелеевМ. А.
Russian Federation

1 Samory Mashela St., Moscow 117198.

1, bldg. 2 Leninskie Gory, Moscow 119991.

4 Kosygina St., Moscow 119991. 

9 Institutskiy Pereulok, Dolgoprudnyi 141700.

Михаил Александрович Пантелеев.

117997 Москва, ул. Саморы Машела, 1.

119991 Москва, Ленинские горы, 1, стр. 2.

119991 Москва, ул. Косыгина, 4.

141700 Долгопрудный, Институтский переулок, 9.

mapanteleev@yandex.ruSveshnikovaA. N.СвешниковаА. Н.
Russian Federation

1 Samory Mashela St., Moscow 117198.

1, bldg. 2 Leninskie Gory, Moscow 119991.

4 Kosygina St., Moscow 119991. 

117997 Москва, ул. Саморы Машела, 1.

119991 Москва, Ленинские горы, 1, стр. 2.

119991 Москва, ул. Косыгина, 4.

Dmitry Rogachev National Medical Research Centre of Pediatric Hematology, Oncology and ImmunologyФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии имени Дмитрия Рогачева» Минздрава РоссииLomonosov Moscow State University, Faculty of PhysicsМосковский государственный университет имени М.В. Ломоносова, физический факультетCenter for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences.Центр теоретических проблем физико-химической фармакологии РАН.Lomonosov Moscow State University, Faculty of Physics.Московский государственный университет имени М.В. Ломоносова, физический факультет.Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of SciencesЦентр теоретических проблем физико-химической фармакологии РАНMoscow Institute of Physics and Technology (State University), Faculty of Biological and Medical Physics.Московский физико-технический институт (государственный университет), факультет биологической и медицинской физики.2710201813383902710201827102018https://oncohematology.abvpress.ru/ongm/article/view/310

Platelet activating receptor CLEC-2 has been identified on platelet surface a decade ago. The only confirmed endogenous CLEC-2 agonist is podoplanin. Podoplanin is a transmembrane protein expressed by lymphatic endothelial cells, reticular fibroblastic cells in lymph nodes, kidney podocytes and by cells of certain tumors. Association of CLEC-2 with podoplanin is involved in processes of embryonic development (blood-lymph vessel separation and angiogenesis), maintaining of vascular integrity of small vessels during inflammation and prevention of blood-lymphatic mixing in high endothelial venules. However, CLEC-2 and podoplanin are contributing to tumor metastasis progression, Salmonella sepsis and deep-vein thrombosis. This makes CLEC-2 and podoplanin a perspective target for pharmacological treatment. Aspirin and Ibrutinib are considered to be perspective for abrogation of podoplanin-induced platelet activation via CLEC-2. The present review discusses already known pathological and physiological roles of CLEC-2 and possibilities of a targeted therapy for CLEC-2 associated diseases.

Рецептор семейства лектиноподобных типа С (C-type lectin-like, CLEC) CLEC-2 был обнаружен на тромбоцитах человека около 10 лет назад. Основным эндогенным лигандом CLEC-2 является мембранный белок подопланин, экспрессируемый клетками эндотелия лимфатических сосудов, ретикулярными фибробластами в лимфатических узлах и подоцитами почечной капсулы. Также подопланин экспонируется на поверхности клеток некоторых опухолей (меланом, глиом). Комплекс CLEC-2–подопланин активно вовлечен в процессы эмбрионального развития (разделение лимфатических и кровеносных сосудов, ангиогенез), поддержания целостности капилляров при воспалительных процессах и предотвращения смешения крови и лимфы в венулах с высоким эндотелием. Также образование комплекса CLEC-2–подопланин происходит при метастазировании некоторых опухолей, сепсисе и развитии тромбозов глубоких вен. Перспективными препаратами из числа существующих для лечения связанных с CLEC-2 заболеваний являются ибрутиниб и аспирин. В настоящем обзоре обсуждаются известные физиологические и патологические возможности CLEC-2 и перспективы таргетной терапии ассоциированных с действием CLEC-2 заболеваний.

plateletmolecular signalingtyrosine-kinasesCLEC-2metastasisdeep vein thrombosisтромбоцитмолекулярная сигнализациятирозинкиназыCLEC-2метастазированиетромбоз глубоких венФазоилу
 Инноятовичу
 Атауллаханову, ЦТП
 ФХФ
 РАНKamkin A., Kamenskiy A. Fundamental and Clinical Physiology. Moscow: Akademia, 2004 (In Russ.).Камкин А., Каменский А. Фундаментальная и клиническая физиология. М.: Академия, 2004.Canobbio I., Balduini C., Torti M. Signalling through the platelet glycoprotein Ib-V–IX complex. Cell Signal 2004;16(12):1329–44. DOI: 10.1016/j.cellsig.2004.05.008. PMID: 15381249.Payrastre B., Missy K., Trumel C. et al. The integrin alpha IIb/beta3 in human platelet signal transduction. Biochem Pharmacol 2000;60(8):1069–74. DOI: 10.1016/S0006-2952(00)00417-2. PMID: 11007943.Coxon C.H., Geer M.J., Senis Y.A. ITIM receptors: More than just inhibitors of platelet activation. Blood 2017;129(26):3407–18. DOI: 10.1182/blood-2016-12-720185. PMID: 28465343.Du X. Self-control of platelets: a new ITIM story. Blood 2014;124(15):2322–3. DOI: 10.1182/blood-2014-08-593830. PMID: 25301334.Watson S.P., Asazuma N., Atkinson B. et al. The Role of ITAM- and ITIM-coupled Receptors in Platelet Activation by Collagen. Thromb Haemost 2001;86(1):276–88. PMID: 11487016.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. DOI: 10.1002/1521-4141(200002) 30:2<697::AID-IMMU697>3.0.CO;2-M. PMID: 10671229.Mourão-Sá D., Robinson M.J., Zelenay S. et al. CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses. Eur J Immunol 2011;41(10):3040–53. DOI: 10.1002/eji.201141641. PMID: 21728173.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(2):219–29. DOI: 10.1111/jth.13590. PMID: 27960039.Astarita J.L., Acton S.E., Turley S.J. Podoplanin: Emerging functions in development, the immune system, and cancer. Front Immunol 2012;3:283. DOI: 10.3389/fimmu.2012.00283. PMID: 22988448.Haining E.J., Cherpokova D., Wolf K. et al. CLEC 2 contributes to hemostasis independently of classical hemITAM signaling in mice. Blood 2017;130(20):2224–8. DOI: 10.1182/blood-2017-03-771907. PMID: 28835437.Takemoto A., Miyata K., Fujita N. Platelet-activating factor podoplanin: from discovery to drug development. Cancer Metastasis Rev 2017;36(2):225–34. DOI: 10.1007/s10555-017-9672-2. PMID: 28674748.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(2):219–29. DOI: 10.1111/jth.13590. PMID: 27960039.Shirai T., Inoue O., Tamura S. et al. Ctype lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice. J Thromb Haemost 2017;15(3):513–25. DOI: 10.1111/jth.13604. PMID: 28028907.Hitchcock J.R., Cook C.N., Bobat S. et al. Cunningham, Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets. J Clin Invest 2015;125(12):4429–46. DOI: 10.1172/JCI79070. PMID: 26571395.Payne H., Ponomaryov T., Watson S.P., Brill A. Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood 2017;129(14):2013–20. DOI: 10.1182/blood-2016-09-742999. PMID: 28104688.Kato Y., Fujita N., Kunita A. et al. Molecular Identification of Aggrus/T1α as a Platelet Aggregation-inducing Factor Expressed in Colorectal Tumors. J Biol Chem 2003;278(51):51599–605. DOI: 10.1074/jbc.M309935200. PMID: 14522983.Kaneko M.K., Kato Y., Kitano T., Osawa M. Conservation of a platelet activating domain of Aggrus/podoplanin as a platelet aggregation-inducing factor. Gene 2006;378:52–7. DOI: 10.1016/j.gene.2006.04.023. PMID: 16766141.Pollitt A.Y., Poulter N.S., Gitz E. et al. Syk and src family kinases regulate c-type lectin receptor 2 (clec-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells. J Biol Chem 2014;289(52):35695–710. DOI: 10.1074/jbc.M114.584284. PMID: 25368330.Shin Y., Morita T. Rhodocytin, a functional novel platelet agonist belonging to the heterodimeric C-type lectin family, induces platelet aggregation independently of glycoprotein Ib. Biochem Biophys Res Commun 1998; 245(3):741–5. DOI: 10.1006/bbrc.1998.8516. PMID: 9588185.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(36):25993–26001. DOI: 10.1074/jbc.M702327200. PMID: 17616532.Watson A.A., Eble J.A., O’Callaghan C.A. Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2. Protein Sci 2008;17(9):1611–6. DOI: 10.1110/ps.035568.108. PMID: 18583525.Nagae M., Morita-Matsumoto K., Kato M. et al. A platform of C-type lectin-like receptor CLEC-2 for binding O-glycosylated podoplanin and nonglycosylated rhodocytin. Structure 2014;22(12):1711–21. DOI: 10.1016/j.str.2014.09.009. PMID: 25458834.Watson A.A., Christou C.M., James J.R. et al. The platelet receptor CLEC-2 is active as a dimer. Biochemistry 2009;48(46):10988–96. DOI: 10.1021/bi901427d. PMID: 19824697.Manne B.K., Getz T.M., Hughes C.E. et al. Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC-2). J Biol Chem 2013;288(11):7717–26. DOI: 10.1074/jbc.M112.424473. PMID: 23341451.Hughes C.E., Sinha U., Pandey A. et al. 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. DOI: 10.1074/jbc.M112.411462. PMID: 23264619.Hughes C.E., Finney B.A., Koentgen F. et al. The N-terminal SH2 domain of Syk is required for (hem) ITAM, but not integrin , signaling in mouse platelets. Blood 2015;125(1):144–55. DOI: 10.1182/blood-2014-05-579375. PMID: 25352128.Pollitt A.Y., Grygielska B., Leblond B. et al. Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization, secondary mediators, and Rac. Blood 2010;115914):2938–2946. DOI: 10.1182/blood-2009-12-257212. PMID: 20154214.Hughes C.E., Pollitt A.Y., Mori J. et al. CLEC-2 activates Syk through dimerization. Blood 2010;115(14):2947–55. DOI: 10.1182/blood-2009-08-237834. PMID: 20154219.Badolia R., Inamdar V., Manne B.K. et al. Gq pathway regulates proximal C-type lectin-like receptor-2(CLEC-2) signaling in platelets. J Biol Chem 2017; 292(35):14516–31. DOI: 10.1074/jbc.M117.791012. PMID: 28705934.Manne B.K., Badolia R., Dangelmaier C. et al. Distinct pathways regulate Syk protein activation downstream of immune tyrosine activation motif (ITAM) and hemITAM receptors in platelets. J Biol Chem 2015;290(18):11557–68. DOI: 10.1074/jbc.M114.629527. PMID: 25767114.Gibbins J.M., Briddon S., Shutes A. et al. The p85 subunit of phosphatidylinositol 3-kinase associates with the Fc receptor gamma chain and linker for activitor of T cells (LAT) in platelets stimulated by collagen and convulxin. J Biol Chem 1998;273(51):34437–43. DOI: 10.1074/jbc.273.51.34437. PMID: 9852111.Manne B.K., Badolia R., Dangelmaier C.A., Kunapuli S.P. C-type lectin like receptor 2 (CLEC-2) signals independently of lipid raft microdomains in platelets. Biochem Pharmacol 2015;93(2):163–70. DOI: 10.1016/j.bcp.2014.11.005. PMID: 25462818.Akinleye A., Chen Y., Mukhi N. et al. Ibrutinib and novel BTK inhibitors in cli nical development. J Hematol Oncol 2013;6:59. DOI: 10.1186/1756-8722-6-59. PMID: