Abstract
Platelets are unique anucleated blood cells that constantly patrol the vasculature to seal and prevent injuries in a process termed haemostasis. Thereby they rapidly adhere to the subendothelial matrix and recruit further platelets, resulting in platelet aggregates. Apart from their central role in haemostasis, they also kept some of their features inherited by their evolutionary ancestor—the haemocyte, which was also involved in immune defences. Together with leukocytes, platelets fight pathogenic invaders and guide many immune processes. In addition, they rely on several signalling pathways which are also relevant to immune cells. Among these, one of the central signalling hubs is the PI3K pathway. Signalling processes in platelets are unique as they lack a nucleus and therefore transcriptional regulation is absent. As a result, PI3K subclasses fulfil distinct roles in platelets compared to other cells. In contrast to leukocytes, the central PI3K subclass in platelet signalling is PI3K class Iβ, which underlines the uniqueness of this cell type and opens new ways for potential platelet-specific pharmacologic inhibition. An overview of platelet function and signalling with emphasis on PI3K subclasses and their respective inhibitors is given in this chapter.
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References
Ahn KC, Jun AJ, Pawar P, Jadhav S, Napier S, McCarty OJ, Konstantopoulos K (2005) Preferential binding of platelets to monocytes over neutrophils under flow. Biochem Biophys Res Commun 329(1):345–355. https://doi.org/10.1016/j.bbrc.2005.01.146
Ambrosio AL, Di Pietro SM (2017) Storage pool diseases illuminate platelet dense granule biogenesis. Platelets 28(2):138–146. https://doi.org/10.1080/09537104.2016.1243789
Ampofo E, Muller I, Dahmke IN, Eichler H, Montenarh M, Menger MD, Laschke MW (2015) Role of protein kinase CK2 in the dynamic interaction of platelets, leukocytes and endothelial cells during thrombus formation. Thromb Res 136(5):996–1006. https://doi.org/10.1016/j.thromres.2015.08.023
Badrnya S, Butler LM, Soderberg-Naucler C, Volf I, Assinger A (2012) Platelets directly enhance neutrophil transmigration in response to oxidised low-density lipoprotein. Thromb Haemost 108(4):719–729. https://doi.org/10.1160/TH12-03-0206
Bellio M, Caux M, Vauclard A, Chicanne G, Gratacap MP, Terrisse AD, Severin S, Payrastre B (2020) Phosphatidylinositol 3 monophosphate metabolizing enzymes in blood platelet production and in thrombosis. Adv Biol Regul 75:100664. https://doi.org/10.1016/j.jbior.2019.100664
Bertovic I, Kurelic R, Milosevic I, Bender M, Krauss M, Haucke V, Jurak Begonja A (2020) Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes. J Thromb Haemost 18(7):1756–1772. https://doi.org/10.1111/jth.14764
Best MG, Vancura A, Wurdinger T (2017) Platelet RNA as a circulating biomarker trove for cancer diagnostics. J Thromb Haemost 15(7):1295–1306. https://doi.org/10.1111/jth.13720
Best MG, Wesseling P, Wurdinger T (2018) Tumor-educated platelets as a noninvasive biomarker source for cancer detection and progression monitoring. Cancer Res 78(13):3407–3412. https://doi.org/10.1158/0008-5472.CAN-18-0887
Bird JE, Smith PL, Bostwick JS, Shipkova P, Schumacher WA (2011) Bleeding response induced by anti-thrombotic doses of a phosphoinositide 3-kinase (PI3K)-beta inhibitor in mice. Thromb Res 127(6):560–564. https://doi.org/10.1016/j.thromres.2011.02.007
Blair TA, Moore SF, Williams CM, Poole AW, Vanhaesebroeck B, Hers I (2014) Phosphoinositide 3-kinases p110alpha and p110beta have differential roles in insulin-like growth factor-1-mediated Akt phosphorylation and platelet priming. Arterioscler Thromb Vasc Biol 34(8):1681–1688. https://doi.org/10.1161/ATVBAHA.114.303954
Blair TA, Moore SF, Walsh TG, Hutchinson JL, Durrant TN, Anderson KE, Poole AW, Hers I (2018) Phosphoinositide 3-kinase p110alpha negatively regulates thrombopoietin-mediated platelet activation and thrombus formation. Cell Signal 50:111–120. https://doi.org/10.1016/j.cellsig.2018.05.005
Bryckaert M, Rosa JP, Denis CV, Lenting PJ (2015) Of von Willebrand factor and platelets. Cell Mol Life Sci 72(2):307–326. https://doi.org/10.1007/s00018-014-1743-8
Canobbio I, Stefanini L, Cipolla L, Ciraolo E, Gruppi C, Balduini C, Hirsch E, Torti M (2009) Genetic evidence for a predominant role of PI3Kbeta catalytic activity in ITAM- and integrin-mediated signaling in platelets. Blood 114(10):2193–2196. https://doi.org/10.1182/blood-2009-03-208074
Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655–1657. https://doi.org/10.1126/science.296.5573.1655
Carrim N, Walsh TG, Consonni A, Torti M, Berndt MC, Metharom P (2014) Role of focal adhesion tyrosine kinases in GPVI-dependent platelet activation and reactive oxygen species formation. PLoS ONE 9(11):e113679. https://doi.org/10.1371/journal.pone.0113679
Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, Cooper JA, Hoekstra MF (1997) p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272(31):19236–19241. https://doi.org/10.1074/jbc.272.31.19236
Chari R, Kim S, Murugappan S, Sanjay A, Daniel JL, Kunapuli SP (2009) Lyn, PKC-delta, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion. Blood 114(14):3056–3063. https://doi.org/10.1182/blood-2008-11-188516
Cipolla L, Consonni A, Guidetti G, Canobbio I, Okigaki M, Falasca M, Ciraolo E, Hirsch E, Balduini C, Torti M (2013) The proline-rich tyrosine kinase Pyk2 regulates platelet integrin alphaIIbbeta3 outside-in signaling. J Thromb Haemost 11(2):345–356. https://doi.org/10.1111/jth.12099
Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M (2002) A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 196(6):753–763. https://doi.org/10.1084/jem.20020805
Consonni A, Cipolla L, Guidetti G, Canobbio I, Ciraolo E, Hirsch E, Falasca M, Okigaki M, Balduini C, Torti M (2012) Role and regulation of phosphatidylinositol 3-kinase beta in platelet integrin alpha2beta1 signaling. Blood 119(3):847–856. https://doi.org/10.1182/blood-2011-07-364992
Cosemans JM, Munnix IC, Wetzker R, Heller R, Jackson SP, Heemskerk JW (2006) Continuous signaling via PI3K isoforms beta and gamma is required for platelet ADP receptor function in dynamic thrombus stabilization. Blood 108(9):3045–3052. https://doi.org/10.1182/blood-2006-03-006338
Dai B, Wu P, Xue F, Yang R, Yu Z, Dai K, Ruan C, Liu G, Newman PJ, Gao C (2016) Integrin-alphaIIbbeta3-mediated outside-in signalling activates a negative feedback pathway to suppress platelet activation. Thromb Haemost 116(5):918–930. https://doi.org/10.1160/TH16-02-0096
Denis MM, Tolley ND, Bunting M, Schwertz H, Jiang H, Lindemann S, Yost CC, Rubner FJ, Albertine KH, Swoboda KJ, Fratto CM, Tolley E, Kraiss LW, McIntyre TM, Zimmerman GA, Weyrich AS (2005) Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 122(3):379–391. https://doi.org/10.1016/j.cell.2005.06.015
Djellas Y, Manganello JM, Antonakis K, Le Breton GC (1999) Identification of Galpha13 as one of the G-proteins that couple to human platelet thromboxane A2 receptors. J Biol Chem 274(20):14325–14330
Eisinger F, Patzelt J, Langer HF (2018) The platelet response to tissue injury. Front Med (lausanne) 5:317. https://doi.org/10.3389/fmed.2018.00317
Feng W, Chang C, Luo D, Su H, Yu S, Hua W, Chen Z, Hu H, Liu W (2014) Dissection of autophagy in human platelets. Autophagy 10(4):642–651. https://doi.org/10.4161/auto.27832
Fong KP, Barry C, Tran AN, Traxler EA, Wannemacher KM, Tang HY, Speicher KD, Blair IA, Speicher DW, Grosser T, Brass LF (2011) Deciphering the human platelet sheddome. Blood 117(1):e15-26. https://doi.org/10.1182/blood-2010-05-283838
Fougerat A, Gayral S, Malet N, Briand-Mesange F, Breton-Douillon M, Laffargue M (2009) Phosphoinositide 3-kinases and their role in inflammation: potential clinical targets in atherosclerosis? Clin Sci (lond) 116(11):791–804. https://doi.org/10.1042/CS20080549
Garcia A, Kim S, Bhavaraju K, Schoenwaelder SM, Kunapuli SP (2010) Role of phosphoinositide 3-kinase beta in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways. Biochem J 429(2):369–377. https://doi.org/10.1042/BJ20100166
Gear AR, Camerini D (2003) Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation 10(3–4):335–350. https://doi.org/10.1038/sj.mn.7800198
Geraldo RB, Sathler PC, Lourenco AL, Saito MS, Cabral LM, Rampelotto PH, Castro HC (2014) Platelets: still a therapeutical target for haemostatic disorders. Int J Mol Sci 15(10):17901–17919. https://doi.org/10.3390/ijms151017901
Ghoshal K, Bhattacharyya M (2014) Overview of platelet physiology: its hemostatic and nonhemostatic role in disease pathogenesis. Sci World J 2014:781857. https://doi.org/10.1155/2014/781857
Gilio K, Munnix IC, Mangin P, Cosemans JM, Feijge MA, van der Meijden PE, Olieslagers S, Chrzanowska-Wodnicka MB, Lillian R, Schoenwaelder S, Koyasu S, Sage SO, Jackson SP, Heemskerk JW (2009) Non-redundant roles of phosphoinositide 3-kinase isoforms alpha and beta in glycoprotein VI-induced platelet signaling and thrombus formation. J Biol Chem 284(49):33750–33762. https://doi.org/10.1074/jbc.M109.048439
Giuriato S, Payrastre B, Drayer AL, Plantavid M, Woscholski R, Parker P, Erneux C, Chap H (1997) Tyrosine phosphorylation and relocation of SHIP are integrin-mediated in thrombin-stimulated human blood platelets. J Biol Chem 272(43):26857–26863. https://doi.org/10.1074/jbc.272.43.26857
Goncalves I, Nesbitt WS, Yuan Y, Jackson SP (2005) Importance of temporal flow gradients and integrin alphaIIbbeta3 mechanotransduction for shear activation of platelets. J Biol Chem 280(15):15430–15437. https://doi.org/10.1074/jbc.M410235200
Grommes J, Alard JE, Drechsler M, Wantha S, Morgelin M, Kuebler WM, Jacobs M, von Hundelshausen P, Markart P, Wygrecka M, Preissner KT, Hackeng TM, Koenen RR, Weber C, Soehnlein O (2012) Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 185(6):628–636. https://doi.org/10.1164/rccm.201108-1533OC
Gutmann C, Joshi A, Zampetaki A, Mayr M (2020) The landscape of coding and noncoding RNAs in platelets. Antioxid Redox Signal. https://doi.org/10.1089/ars.2020.8139
Hall KJ, Jones ML, Poole AW (2007) Coincident regulation of PKCdelta in human platelets by phosphorylation of Tyr311 and Tyr565 and phospholipase C signalling. Biochem J 406(3):501–509. https://doi.org/10.1042/bj20070244
Harada K, Truong AB, Cai T, Khavari PA (2005) The class II phosphoinositide 3-kinase C2beta is not essential for epidermal differentiation. Mol Cell Biol 25(24):11122–11130. https://doi.org/10.1128/MCB.25.24.11122-11130.2005
Harrison P, Goodall AH (2008) “Message in the platelet”–more than just vestigial mRNA! Platelets 19(6):395–404. https://doi.org/10.1080/09537100801990582
Hechler B, Leon C, Vial C, Vigne P, Frelin C, Cazenave JP, Gachet C (1998) The P2Y1 receptor is necessary for adenosine 5′-diphosphate-induced platelet aggregation. Blood 92(1):152–159
Hers I (2007) Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kalpha pathway. Blood 110(13):4243–4252. https://doi.org/10.1182/blood-2006-10-050633
Hirsch E, Bosco O, Tropel P, Laffargue M, Calvez R, Altruda F, Wymann M, Montrucchio G (2001) Resistance to thromboembolism in PI3Kgamma-deficient mice. FASEB J 15(11):2019–2021. https://doi.org/10.1096/fj.00-0810fje
Holmsen H, Dangelmaier CA (1989) Measurement of secretion of lysosomal acid glycosidases. Methods Enzymol 169:336–342
Jackson SP (2011) Arterial thrombosis–insidious, unpredictable and deadly. Nat Med 17(11):1423–1436. https://doi.org/10.1160/TH07-07-0452
Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones C, Lu L, Giuliano S, Hughan SC, Angus JA, Robertson AD, Salem HH (2005) PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 11(5):507–514. https://doi.org/10.1038/nm1232
Kahner BN, Shankar H, Murugappan S, Prasad GL, Kunapuli SP (2006) Nucleotide receptor signaling in platelets. J Thromb Haemost 4(11):2317–2326. https://doi.org/10.1111/j.1538-7836.2006.02192.x
Kim S, Jin J, Kunapuli SP (2006) Relative contribution of G-protein-coupled pathways to protease-activated receptor-mediated Akt phosphorylation in platelets. Blood 107(3):947–954. https://doi.org/10.1182/blood-2005-07-3040
Kim S, Garcia A, Jackson SP, Kunapuli SP (2007) Insulin-like growth factor-1 regulates platelet activation through PI3-Kalpha isoform. Blood 110(13):4206–4213. https://doi.org/10.1182/blood-2007-03-080804
Kim S, Mangin P, Dangelmaier C, Lillian R, Jackson SP, Daniel JL, Kunapuli SP (2009) Role of phosphoinositide 3-kinase beta in glycoprotein VI-mediated Akt activation in platelets. J Biol Chem 284(49):33763–33772. https://doi.org/10.1074/jbc.M109.048553
Krajewski S, Kurz J, Geisler T, Peter K, Wendel HP, Straub A (2012) Combined blockade of ADP receptors and PI3-kinase p110beta fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation. PLoS ONE 7(6):e38455. https://doi.org/10.1371/journal.pone.0038455
Kral JB, Schrottmaier WC, Salzmann M, Assinger A (2016) Platelet interaction with innate immune cells. Transfus Med Hemother 43(2):78–88. https://doi.org/10.1159/000444807
Kral-Pointner JB, Schrottmaier WC, Salzmann M, Mussbacher M, Schmidt GJ, Moser B, Heber S, Birnecker B, Paar H, Zellner M, Knapp S, Assinger A, Schabbauer G (2019) Platelet PI3K modulates innate Leukocyte extravasation during acid-induced acute lung inflammation. Thromb Haemost 119(10):1642–1654. https://doi.org/10.1055/s-0039-1693693
Krugmann S, Hawkins PT, Pryer N, Braselmann S (1999) Characterizing the interactions between the two subunits of the p101/p110gamma phosphoinositide 3-kinase and their role in the activation of this enzyme by G beta gamma subunits. J Biol Chem 274(24):17152–17158
Kuijpers MJ, Mattheij NJ, Cipolla L, van Geffen JP, Lawrence T, Donners MM, Boon L, Lievens D, Torti M, Noels H, Gerdes N, Cosemans JM, Lutgens E, Heemskerk JW (2015) Platelet CD40L modulates thrombus growth via Phosphatidylinositol 3-Kinase beta, and not via CD40 and IkappaB Kinase alpha. Arterioscler Thromb Vasc Biol 35(6):1374–1381. https://doi.org/10.1161/ATVBAHA.114.305127
Kurosu H, Maehama T, Okada T, Yamamoto T, Hoshino S, Fukui Y, Ui M, Hazeki O, Katada T (1997) Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110beta is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl peptide. J Biol Chem 272(39):24252–24256
Laurent PA, Severin S, Gratacap MP, Payrastre B (2014) Class I PI 3-kinases signaling in platelet activation and thrombosis: PDK1/Akt/GSK3 axis and impact of PTEN and SHIP1. Adv Biol Regul 54:162–174. https://doi.org/10.1016/j.jbior.2013.09.006
Laurent PA, Severin S, Hechler B, Vanhaesebroeck B, Payrastre B, Gratacap MP (2015) Platelet PI3Kbeta and GSK3 regulate thrombus stability at a high shear rate. Blood 125(5):881–888. https://doi.org/10.1182/blood-2014-07-588335
Laurent PA, Hechler B, Solinhac R, Ragab A, Cabou C, Anquetil T, Severin S, Denis CV, Mangin PH, Vanhaesebroeck B, Payrastre B, Gratacap MP (2018) Impact of PI3Kalpha (Phosphoinositide 3-Kinase Alpha) inhibition on hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 38(9):2041–2053. https://doi.org/10.1161/ATVBAHA.118.311410
Levin J (2013) Chapter 1—the evolution of mammalian platelets. In: Michelson AD (ed) Platelets, 3rd edn. Academic Press, pp 3–25. https://doi.org/10.1016/B978-0-12-387837-3.00001-8
Li Z, Delaney MK, O’Brien KA, Du X (2010) Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol 30(12):2341–2349. https://doi.org/10.1161/atvbaha.110.207522
Lian L, Wang Y, Draznin J, Eslin D, Bennett JS, Poncz M, Wu D, Abrams CS (2005) The relative role of PLCbeta and PI3Kgamma in platelet activation. Blood 106(1):110–117. https://doi.org/10.1182/blood-2004-05-2005
Licari LG, Kovacic JP (2009) Thrombin physiology and pathophysiology. J Veterinary Emergency Critical Care (San Antonio, Tex: 2001) 19(1):11–22. https://doi.org/10.1111/j.1476-4431.2009.00383.x
Liu Y, Hu M, Luo D, Yue M, Wang S, Chen X, Zhou Y, Wang Y, Cai Y, Hu X, Ke Y, Yang Z, Hu H (2017) Class III PI3K positively regulates platelet activation and thrombosis via PI(3)P-directed function of NADPH oxidase. Arterioscler Thromb Vasc Biol 37(11):2075–2086. https://doi.org/10.1161/ATVBAHA.117.309751
M.D. Anderson Cancer Center, National Cancer Institute, National Institutes of Health, Merck Sharp, Dohme Corp., GlaxoSmithKline (2017) Study of the selective PI3K-Beta Inhibitor GSK2636771 in combination with Pembrolizumab in patients with metastatic melanoma and PTEN loss. https://ClinicalTrials.gov/show/NCT03131908
Machlus KR, Thon JN, Italiano JE Jr (2014) Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation. Br J Haematol 165(2):227–236. https://doi.org/10.1111/bjh.12758
Manganaro D, Consonni A, Guidetti GF, Canobbio I, Visconte C, Kim S, Okigaki M, Falasca M, Hirsch E, Kunapuli SP, Torti M (2015) Activation of phosphatidylinositol 3-kinase beta by the platelet collagen receptors integrin alpha2beta1 and GPVI: the role of Pyk2 and c-Cbl. Biochim Biophys Acta 1853(8):1879–1888. https://doi.org/10.1016/j.bbamcr.2015.05.004
Martin V, Guillermet-Guibert J, Chicanne G, Cabou C, Jandrot-Perrus M, Plantavid M, Vanhaesebroeck B, Payrastre B, Gratacap MP (2010) Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood 115(10):2008–2013. https://doi.org/10.1182/blood-2009-04-217224
Moore SF, Smith NR, Blair TA, Durrant TN, Hers I (2019) Critical roles for the phosphatidylinositide 3-kinase isoforms p110beta and p110gamma in thrombopoietin-mediated priming of platelet function. Sci Rep 9(1):1468. https://doi.org/10.1038/s41598-018-37012-9
Moser M, Nieswandt B, Ussar S, Pozgajova M, Fassler R (2008) Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 14(3):325–330. https://doi.org/10.1038/nm1722
Mountford JK, Petitjean C, Putra HW, McCafferty JA, Setiabakti NM, Lee H, Tonnesen LL, McFadyen JD, Schoenwaelder SM, Eckly A, Gachet C, Ellis S, Voss AK, Dickins RA, Hamilton JR, Jackson SP (2015) The class II PI 3-kinase, PI3KC2alpha, links platelet internal membrane structure to shear-dependent adhesive function. Nat Commun 6:6535. https://doi.org/10.1038/ncomms7535
National Cancer Institute (2018) PI3Kbeta inhibitor AZD8186 and docetaxel in treating patients advanced solid tumors with PTEN or PIK3CB mutations that are metastatic or cannot be removed by surgery. https://ClinicalTrials.gov/show/NCT03218826
Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, Riddle S, Benes C, Eck M, Roberts T, Gray N, Zhao J (2012) Functional characterization of an isoform-selective inhibitor of PI3K-p110beta as a potential anticancer agent. Cancer Discov 2(5):425–433. https://doi.org/10.1158/2159-8290.CD-12-0003
Nylander S, Kull B, Bjorkman JA, Ulvinge JC, Oakes N, Emanuelsson BM, Andersson M, Skarby T, Inghardt T, Fjellstrom O, Gustafsson D (2012) Human target validation of phosphoinositide 3-kinase (PI3K)beta: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kbeta inhibitor. J Thromb Haemost 10(10):2127–2136. https://doi.org/10.1111/j.1538-7836.2012.04898.x
Nylander S, Wagberg F, Andersson M, Skarby T, Gustafsson D (2015) Exploration of efficacy and bleeding with combined phosphoinositide 3-kinase beta inhibition and aspirin in man. J Thromb Haemost 13(8):1494–1502. https://doi.org/10.1111/jth.13027
Offermanns S (2006) Activation of platelet function through G protein-coupled receptors. Circ Res 99(12):1293–1304. https://doi.org/10.1161/01.res.0000251742.71301.16
Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297(5583):1031–1034. https://doi.org/10.1126/science.1073560
Pasquet JM, Quek L, Stevens C, Bobe R, Huber M, Duronio V, Krystal G, Watson SP (2000) Phosphatidylinositol 3,4,5-trisphosphate regulates Ca(2+) entry via btk in platelets and megakaryocytes without increasing phospholipase C activity. EMBO J 19(12):2793–2802. https://doi.org/10.1093/emboj/19.12.2793
Pavlovic V, Ciric M, Jovanovic V, Stojanovic P (2016) Platelet rich plasma: a short overview of certain bioactive components. Open Med (wars) 11(1):242–247. https://doi.org/10.1515/med-2016-0048
Petitjean C, Setiabakti NM, Mountford JK, Arthur JF, Ellis S, Hamilton JR (2016) Combined deficiency of PI3KC2alpha and PI3KC2beta reveals a nonredundant role for PI3KC2alpha in regulating mouse platelet structure and thrombus stability. Platelets 27(5):402–409. https://doi.org/10.3109/09537104.2016.1145202
Ramackers W, Rataj D, Werwitzke S, Bergmann S, Winkler M, Wunsch A, Bahr A, Wolf E, Klymiuk N, Ayares D, Tiede A (2020) Expression of human thrombomodulin on porcine endothelial cells can reduce platelet aggregation but did not reduce activation of complement or endothelium—an experimental study. Transpl Int 33(4):437–449. https://doi.org/10.1111/tri.13573
Schrottmaier WC, Kral JB, Badrnya S, Assinger A (2015) Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes. Thromb Haemost 114(3):478–489. https://doi.org/10.1160/TH14-11-0943
Schrottmaier WC, Mussbacher M, Salzmann M, Assinger A (2020) Platelet-leukocyte interplay during vascular disease. Atherosclerosis 307:109–120. https://doi.org/10.1016/j.atherosclerosis.2020.04.018
Schrottmaier WC, Salzmann M, Badrnya S, Mussbacher M, Kral-Pointner JB, Morava S, Pirabe A, Brunnthaler L, Yaiw KC, Heber UM, Pereyra D, Andersen JT, Bergthaler A, Söderberg-Nauclér C, Karlsson MCI, Assinger A, Forsell MNE (2020 Aug) Platelets mediate serological memory to neutralize viruses in vitro and in vivo. Blood Adv 25;4(16):3971–3976, PMID: 32841338. https://doi.org/10.1182/bloodadvances.2020001786
Schwertz H, Tolley ND, Foulks JM, Denis MM, Risenmay BW, Buerke M, Tilley RE, Rondina MT, Harris EM, Kraiss LW, Mackman N, Zimmerman GA, Weyrich AS (2006) Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med 203(11):2433–2440. https://doi.org/10.1084/jem.20061302
Selvadurai MV, Brazilek RJ, Moon MJ, Rinckel JY, Eckly A, Gachet C, Meikle PJ, Nandurkar HH, Nesbitt WS, Hamilton JR (2019) The PI 3-kinase PI3KC2alpha regulates mouse platelet membrane structure and function independently of membrane lipid composition. FEBS Lett 593(1):88–96. https://doi.org/10.1002/1873-3468.13295
Selvadurai MV, Moon MJ, Mountford SJ, Ma X, Zheng Z, Jennings IG, Setiabakti NM, Iman RP, Brazilek RJ, NA ZA, Chicanne G, Severin S, Nicholls AJ, Wong CHY, Rinckel JY, Eckly A, Gachet C, Nesbitt WS, Thompson PE, Hamilton JR (2020) Disrupting the platelet internal membrane via PI3KC2alpha inhibition impairs thrombosis independently of canonical platelet activation. Sci Transl Med 12(553). https://doi.org/10.1126/scitranslmed.aar8430
Senis YA, Atkinson BT, Pearce AC, Wonerow P, Auger JM, Okkenhaug K, Pearce W, Vigorito E, Vanhaesebroeck B, Turner M, Watson SP (2005) Role of the p110delta PI 3-kinase in integrin and ITAM receptor signalling in platelets. Platelets 16(3–4):191–202. https://doi.org/10.1080/09537100400016711
Senis YA, Mazharian A, Mori J (2014) Src family kinases: at the forefront of platelet activation. Blood 124(13):2013–2024. https://doi.org/10.1182/blood-2014-01-453134
Shattil SJ, Newman PJ (2004) Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 104(6):1606–1615. https://doi.org/10.1182/blood-2004-04-1257
Sorrentino S, Studt JD, Medalia O, Tanuj Sapra K (2015) Roll, adhere, spread and contract: structural mechanics of platelet function. Eur J Cell Biol 94(3–4):129–138. https://doi.org/10.1016/j.ejcb.2015.01.001
Spater T, Muller I, Eichler H, Menger MD, Laschke MW, Ampofo E (2018) Dual inhibition of PI3K and mTOR by VS-5584 suppresses thrombus formation. Platelets 29(3):277–287. https://doi.org/10.1080/09537104.2017.1306040
Stefanini L, Bergmeier W (2016) RAP1-GTPase signaling and platelet function. J Mol Med (berl) 94(1):13–19. https://doi.org/10.1007/s00109-015-1346-3
Stephen J, Emerson B, Fox KA, Dransfield I (2013) The uncoupling of monocyte-platelet interactions from the induction of proinflammatory signaling in monocytes. J Immunol 191(11):5677–5683. https://doi.org/10.4049/jimmunol.1301250
Stoiber D, Assinger A (2020) Platelet-Leukocyte interplay in cancer development and progression. Cells 9(4). https://doi.org/10.3390/cells9040855
Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S (2000) The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 110(4):925–934
Sturgeon SA, Jones C, Angus JA, Wright CE (2008) Advantages of a selective beta-isoform phosphoinositide 3-kinase antagonist, an anti-thrombotic agent devoid of other cardiovascular actions in the rat. Eur J Pharmacol 587(1–3):209–215. https://doi.org/10.1016/j.ejphar.2008.03.017
Tang X, Downes CP (1997) Purification and characterization of Gbetagamma-responsive phosphoinositide 3-kinases from pig platelet cytosol. J Biol Chem 272(22):14193–14199
Terrisse AD, Laurent PA, Garcia C, Gratacap MP, Vanhaesebroeck B, Sie P, Payrastre B (2016) The class I phosphoinositide 3-kinases alpha and beta control antiphospholipid antibodies-induced platelet activation. Thromb Haemost 115(6):1138–1146. https://doi.org/10.1160/TH15-08-0661
Torti M, Manganaro D, Visconte C, Zara M, Canino J, Vismara M, Canobbio I, Guidetti GF (2020) Stimulation of mTORC2 by integrin alphaIIbbeta3 is required for PI3Kbeta-dependent activation of Akt but is dispensable for platelet spreading on fibrinogen. Platelets 31(4):521–529. https://doi.org/10.1080/09537104.2019.1663806
Valet C, Chicanne G, Severac C, Chaussade C, Whitehead MA, Cabou C, Gratacap MP, Gaits-Iacovoni F, Vanhaesebroeck B, Payrastre B, Severin S (2015) Essential role of class II PI3K-C2alpha in platelet membrane morphology. Blood 126(9):1128–1137. https://doi.org/10.1182/blood-2015-03-636670
Valet C, Levade M, Chicanne G, Bilanges B, Cabou C, Viaud J, Gratacap MP, Gaits-Iacovoni F, Vanhaesebroeck B, Payrastre B, Severin S (2017) A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth. Blood 130(18):2032–2042. https://doi.org/10.1182/blood-2017-04-781641
van der Meijden PE, Schoenwaelder SM, Feijge MA, Cosemans JM, Munnix IC, Wetzker R, Heller R, Jackson SP, Heemskerk JW (2008) Dual P2Y 12 receptor signaling in thrombin-stimulated platelets–involvement of phosphoinositide 3-kinase beta but not gamma isoform in Ca2+ mobilization and procoagulant activity. FEBS J 275(2):371–385. https://doi.org/10.1111/j.1742-4658.2007.06207.x
Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD (1997) P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A 94(9):4330–4335
Vanhaesebroeck B, Whitehead MA, Pineiro R (2016) Molecules in medicine mini-review: isoforms of PI3K in biology and disease. J Mol Med (berl) 94(1):5–11. https://doi.org/10.1007/s00109-015-1352-5
Wang C, Jin R, Nanda A, Yan J, Li G (2015) Platelet PI3Kgamma contributes to carotid intima-media thickening under severely reduced flow conditions. PLoS ONE 10(6):e0129265. https://doi.org/10.1371/journal.pone.0129265
Watanabe N, Nakajima H, Suzuki H, Oda A, Matsubara Y, Moroi M, Terauchi Y, Kadowaki T, Suzuki H, Koyasu S, Ikeda Y, Handa M (2003) Functional phenotype of phosphoinositide 3-kinase p85alpha-null platelets characterized by an impaired response to GP VI stimulation. Blood 102(2):541–548. https://doi.org/10.1182/blood-2002-11-3327
Weng Z, Li D, Zhang L, Chen J, Ruan C, Chen G, Gartner TK, Liu J (2010) PTEN regulates collagen-induced platelet activation. Blood 116(14):2579–2581. https://doi.org/10.1182/blood-2010-03-277236
Weyrich AS, Dixon DA, Pabla R, Elstad MR, McIntyre TM, Prescott SM, Zimmerman GA (1998) Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets. Proc Natl Acad Sci U S A 95(10):5556–5561
White JG (2013) Chapter 7—platelet structure. In: Michelson AD (ed) Platelets, 3rd edn. Academic Press, pp 117–144. https://doi.org/10.1016/B978-0-12-387837-3.00007-9
Woulfe D, Jiang H, Mortensen R, Yang J, Brass LF (2002) Activation of Rap1B by G(i) family members in platelets. J Biol Chem 277(26):23382–23390. https://doi.org/10.1074/jbc.M202212200
Woulfe D, Jiang H, Morgans A, Monks R, Birnbaum M, Brass LF (2004) Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2. J Clin Invest 113(3):441–450. https://doi.org/10.1172/JCI20267
Yoshioka K, Yoshida K, Cui H, Wakayama T, Takuwa N, Okamoto Y, Du W, Qi X, Asanuma K, Sugihara K, Aki S, Miyazawa H, Biswas K, Nagakura C, Ueno M, Iseki S, Schwartz RJ, Okamoto H, Sasaki T, Matsui O, Asano M, Adams RH, Takakura N, Takuwa Y (2012) Endothelial PI3K-C2alpha, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat Med 18(10):1560–1569. https://doi.org/10.1038/nm.2928
Yeaman MR (2014 Jun) Platelets: at the nexus of antimicrobial defence. Nat Rev Microbiol 12(6):426–37, PMID: 24830471. https://doi.org/10.1038/nrmicro3269
Zhang J, Vanhaesebroeck B, Rittenhouse SE (2002) Human platelets contain p110delta phosphoinositide 3-kinase. Biochem Biophys Res Commun 296(1):178–181
Zucker M, Hauschner H, Seligsohn U, Rosenberg N (2018) Platelet factor XI: intracellular localization and mRNA splicing following platelet activation. Blood Cells Mol Dis 69:30–37. https://doi.org/10.1016/j.bcmd.2017.04.006
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Schrottmaier, W.C., Mussbacher, M., Salzmann, M., Kral-Pointner, J.B., Assinger, A. (2022). PI3K Isoform Signalling in Platelets. In: Dominguez-Villar, M. (eds) PI3K and AKT Isoforms in Immunity . Current Topics in Microbiology and Immunology, vol 436. Springer, Cham. https://doi.org/10.1007/978-3-031-06566-8_11
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