{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T23:57:42Z","timestamp":1790467062090,"version":"4.1.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Grant-in-Aid for Scientific Researc","award":["19K08314"],"award-info":[{"award-number":["19K08314"]}]},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"crossref","award":["JP20ek0109398h0003"],"award-info":[{"award-number":["JP20ek0109398h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Macrothrombocytopenia is a common pathology of missense mutations in genes regulating actin dynamics. Takenouchi-Kosaki syndrome (TKS) harboring the c.191A\u2009&gt;\u2009G, Tyr64Cys (Y64C) variant in Cdc42 exhibits a variety of clinical manifestations, including immunological and hematological anomalies. In the present study, we investigated the functional abnormalities of the Y64C mutant in HEK293 cells and elucidated the mechanism of macrothrombocytopenia, one of the symptoms of TKS patients, by monitoring the production of platelet-like particles (PLP) using MEG-01 cells. We found that the Y64C mutant was concentrated at the membrane compartment due to impaired binding to Rho-GDI and more active than the wild-type. The Y64C mutant also had lower association with its effectors Pak1\/2 and N-WASP. Y64C mutant-expressing MEG-01 cells demonstrated short cytoplasmic protrusions with aberrant F-actin and microtubules, and reduced PLP production. This suggested that the Y64C mutant facilitates its activity and membrane localization, resulting in impaired F-actin dynamics for proplatelet extension, which is necessary for platelet production. Furthermore, such dysfunction was ameliorated by either suppression of Cdc42 activity or prenylation using chemical inhibitors. Our study may lead to pharmacological treatments for TKS patients.<\/jats:p>","DOI":"10.1038\/s41598-021-97478-y","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T10:06:24Z","timestamp":1631181984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Macrothrombocytopenia of Takenouchi-Kosaki syndrome is ameliorated by CDC42 specific- and lipidation inhibitors in MEG-01 cells"],"prefix":"10.1038","volume":"11","author":[{"given":"Etsuko","family":"Daimon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinao","family":"Shibukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suganya","family":"Thanasegaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuko","family":"Yamazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"97478_CR1","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1242\/jcs.01115","volume":"117","author":"S Etienne-Manneville","year":"2004","unstructured":"Etienne-Manneville, S. Cdc42\u2013the centre of polarity. J. Cell Sci. 117, 1291\u20131300. https:\/\/doi.org\/10.1242\/jcs.01115 (2004).","journal-title":"J. Cell Sci."},{"key":"97478_CR2","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.ceb.2015.08.005","volume":"36","author":"AJ Ridley","year":"2015","unstructured":"Ridley, A. J. Rho GTPase signalling in cell migration. Curr. Opin. Cell Biol. 36, 103\u2013112. https:\/\/doi.org\/10.1016\/j.ceb.2015.08.005 (2015).","journal-title":"Curr. Opin. Cell Biol."},{"key":"97478_CR3","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.217869","author":"F Pichaud","year":"2019","unstructured":"Pichaud, F., Walther, R. F. & Nunes, de, A. F. Regulation of Cdc42 and its effectors in epithelial morphogenesis. J. Cell Sci. https:\/\/doi.org\/10.1242\/jcs.217869 (2019).","journal-title":"J. Cell Sci."},{"key":"97478_CR4","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1038\/sj.embor.7400293","volume":"5","author":"R Dvorsky","year":"2004","unstructured":"Dvorsky, R. & Ahmadian, M. R. Always look on the bright site of Rho: structural implications for a conserved intermolecular interface. EMBO Rep. 5, 1130\u20131136. https:\/\/doi.org\/10.1038\/sj.embor.7400293 (2004).","journal-title":"EMBO Rep."},{"key":"97478_CR5","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1083\/jcb.152.1.111","volume":"152","author":"D Michaelson","year":"2001","unstructured":"Michaelson, D. et al. Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J. Cell Biol. 152, 111\u2013126. https:\/\/doi.org\/10.1083\/jcb.152.1.111 (2001).","journal-title":"J. Cell Biol."},{"key":"97478_CR6","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.ajhg.2017.12.015","volume":"102","author":"S Martinelli","year":"2018","unstructured":"Martinelli, S. et al. Functional dysregulation of CDC42 causes diverse developmental phenotypes. Am. J. Hum. Genet. 102, 309\u2013320. https:\/\/doi.org\/10.1016\/j.ajhg.2017.12.015 (2018).","journal-title":"Am. J. Hum. Genet."},{"key":"97478_CR7","doi-asserted-by":"publisher","first-page":"2371","DOI":"10.1182\/blood-2006-10-055087","volume":"110","author":"BT Kile","year":"2007","unstructured":"Kile, B. T. et al. Mutations in the cofilin partner Aip1\/Wdr1 cause autoinflammatory disease and macrothrombocytopenia. Blood 110, 2371\u20132380. https:\/\/doi.org\/10.1182\/blood-2006-10-055087 (2007).","journal-title":"Blood"},{"key":"97478_CR8","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s13578-015-0029-7","volume":"5","author":"AC Murphy","year":"2015","unstructured":"Murphy, A. C. & Young, P. W. The actinin family of actin cross-linking proteins-a genetic perspective. Cell Biosci. 5, 49. https:\/\/doi.org\/10.1186\/s13578-015-0029-7 (2015).","journal-title":"Cell Biosci."},{"key":"97478_CR9","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1182\/blood-2018-07-861427","volume":"133","author":"A Donada","year":"2019","unstructured":"Donada, A. et al. Disrupted filamin A\/alphaIIbbeta3 interaction induces macrothrombocytopenia by increasing RhoA activity. Blood 133, 1778\u20131788. https:\/\/doi.org\/10.1182\/blood-2018-07-861427 (2019).","journal-title":"Blood"},{"key":"97478_CR10","doi-asserted-by":"publisher","first-page":"2903","DOI":"10.1182\/blood-2015-10-675629","volume":"127","author":"S Stritt","year":"2016","unstructured":"Stritt, S. et al. A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood 127, 2903\u20132914. https:\/\/doi.org\/10.1182\/blood-2015-10-675629 (2016).","journal-title":"Blood"},{"key":"97478_CR11","doi-asserted-by":"publisher","first-page":"2822","DOI":"10.1002\/ajmg.a.37275","volume":"167A","author":"T Takenouchi","year":"2015","unstructured":"Takenouchi, T., Kosaki, R., Niizuma, T., Hata, K. & Kosaki, K. Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay. Am. J. Med. Genet. A 167A, 2822\u20132825. https:\/\/doi.org\/10.1002\/ajmg.a.37275 (2015).","journal-title":"Am. J. Med. Genet. A"},{"key":"97478_CR12","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s10038-017-0396-5","volume":"63","author":"M Motokawa","year":"2018","unstructured":"Motokawa, M. et al. A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome. J. Hum. Genet. 63, 387\u2013390. https:\/\/doi.org\/10.1038\/s10038-017-0396-5 (2018).","journal-title":"J. Hum. Genet."},{"key":"97478_CR13","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.1084\/jem.20190147","volume":"216","author":"MT Lam","year":"2019","unstructured":"Lam, M. T. et al. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. J. Exp. Med. 216, 2778\u20132799. https:\/\/doi.org\/10.1084\/jem.20190147 (2019).","journal-title":"J. Exp. Med."},{"key":"97478_CR14","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1002\/ajmg.a.37526","volume":"170A","author":"T Takenouchi","year":"2016","unstructured":"Takenouchi, T., Okamoto, N., Ida, S., Uehara, T. & Kosaki, K. Further evidence of a mutation in CDC42 as a cause of a recognizable syndromic form of thrombocytopenia. Am. J. Med. Genet. A 170A, 852\u2013855. https:\/\/doi.org\/10.1002\/ajmg.a.37526 (2016).","journal-title":"Am. J. Med. Genet. A"},{"key":"97478_CR15","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1007\/s10875-020-00742-5","volume":"40","author":"G Bucciol","year":"2020","unstructured":"Bucciol, G. et al. Systemic Inflammation and Myelofibrosis in a Patient with Takenouchi-Kosaki Syndrome due to CDC42 Tyr64Cys Mutation. J. Clin. Immunol. 40, 567\u2013570. https:\/\/doi.org\/10.1007\/s10875-020-00742-5 (2020).","journal-title":"J. Clin. Immunol."},{"key":"97478_CR16","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/j.bbrc.2020.06.104","volume":"529","author":"N Hamada","year":"2020","unstructured":"Hamada, N. et al. Neuropathophysiological significance of the c.1449T>C\/p.(Tyr64Cys) mutation in the CDC42 gene responsible for Takenouchi-Kosaki syndrome. Biochem. Biophys. Res. Commun. 529, 1033\u20131037. https:\/\/doi.org\/10.1016\/j.bbrc.2020.06.104 (2020).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"97478_CR17","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1002\/jcp.10035","volume":"190","author":"K Ravid","year":"2002","unstructured":"Ravid, K., Lu, J., Zimmet, J. M. & Jones, M. R. Roads to polyploidy: the megakaryocyte example. J. Cell. Physiol. 190, 7\u201320. https:\/\/doi.org\/10.1002\/jcp.10035 (2002).","journal-title":"J. Cell. Physiol."},{"key":"97478_CR18","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1182\/blood-2013-03-492330","volume":"123","author":"A Eckly","year":"2014","unstructured":"Eckly, A. et al. Biogenesis of the demarcation membrane system (DMS) in megakaryocytes. Blood 123, 921\u2013930. https:\/\/doi.org\/10.1182\/blood-2013-03-492330 (2014).","journal-title":"Blood"},{"key":"97478_CR19","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1083\/jcb.147.6.1299","volume":"147","author":"JE Italiano Jr","year":"1999","unstructured":"Italiano, J. E. Jr., Lecine, P., Shivdasani, R. A. & Hartwig, J. H. Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. J. Cell Biol. 147, 1299\u20131312. https:\/\/doi.org\/10.1083\/jcb.147.6.1299 (1999).","journal-title":"J. Cell Biol."},{"key":"97478_CR20","doi-asserted-by":"publisher","first-page":"3364","DOI":"10.1182\/blood-2009-09-242271","volume":"115","author":"I Pleines","year":"2010","unstructured":"Pleines, I. et al. Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets. Blood 115, 3364\u20133373. https:\/\/doi.org\/10.1182\/blood-2009-09-242271 (2010).","journal-title":"Blood"},{"key":"97478_CR21","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1111\/jth.13318","volume":"14","author":"A Antkowiak","year":"2016","unstructured":"Antkowiak, A. et al. Cdc42-dependent F-actin dynamics drive structuration of the demarcation membrane system in megakaryocytes. J. Thrombosis Haemostasis JTH 14, 1268\u20131284. https:\/\/doi.org\/10.1111\/jth.13318 (2016).","journal-title":"J. Thrombosis Haemostasis JTH"},{"key":"97478_CR22","doi-asserted-by":"publisher","first-page":"15838","DOI":"10.1038\/ncomms15838","volume":"8","author":"S Dutting","year":"2017","unstructured":"Dutting, S. et al. A Cdc42\/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. Nat. Commun. 8, 15838. https:\/\/doi.org\/10.1038\/ncomms15838 (2017).","journal-title":"Nat. Commun."},{"key":"97478_CR23","doi-asserted-by":"publisher","first-page":"2524","DOI":"10.1111\/jth.13519","volume":"14","author":"A Palazzo","year":"2016","unstructured":"Palazzo, A. et al. The cell division control protein 42-Src family kinase-neural Wiskott-Aldrich syndrome protein pathway regulates human proplatelet formation. J. Thrombosis Haemostasis JTH 14, 2524\u20132535. https:\/\/doi.org\/10.1111\/jth.13519 (2016).","journal-title":"J. Thrombosis Haemostasis JTH"},{"key":"97478_CR24","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1046\/j.1365-2141.1998.00576.x","volume":"100","author":"K Takeuchi","year":"1998","unstructured":"Takeuchi, K. et al. Platelet-like particle formation in the human megakaryoblastic leukaemia cell lines, MEG-01 and MEG-01s. Br. J. Haematol. 100, 436\u2013444. https:\/\/doi.org\/10.1046\/j.1365-2141.1998.00576.x (1998).","journal-title":"Br. J. Haematol."},{"key":"97478_CR25","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1385\/1-59259-650-9:429","volume":"246","author":"H Miyoshi","year":"2004","unstructured":"Miyoshi, H. Gene delivery to hematopoietic stem cells using lentiviral vectors. Methods Mol. Biol. 246, 429\u2013438. https:\/\/doi.org\/10.1385\/1-59259-650-9:429 (2004).","journal-title":"Methods Mol. Biol."},{"key":"97478_CR26","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/s0092-8674(00)80670-4","volume":"100","author":"GR Hoffman","year":"2000","unstructured":"Hoffman, G. R., Nassar, N. & Cerione, R. A. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 100, 345\u2013356. https:\/\/doi.org\/10.1016\/s0092-8674(00)80670-4 (2000).","journal-title":"Cell"},{"key":"97478_CR27","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nrm3153","volume":"12","author":"R Garcia-Mata","year":"2011","unstructured":"Garcia-Mata, R., Boulter, E. & Burridge, K. The \u201cinvisible hand\u201d: regulation of RHO GTPases by RHOGDIs. Nat. Rev. Mol. Cell Biol. 12, 493\u2013504. https:\/\/doi.org\/10.1038\/nrm3153 (2011).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"97478_CR28","doi-asserted-by":"publisher","first-page":"3938","DOI":"10.4161\/15384101.2014.982941","volume":"13","author":"V Gasperi","year":"2014","unstructured":"Gasperi, V. et al. 2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts. Cell Cycle 13, 3938\u20133947. https:\/\/doi.org\/10.4161\/15384101.2014.982941 (2014).","journal-title":"Cell Cycle"},{"key":"97478_CR29","doi-asserted-by":"publisher","first-page":"648","DOI":"10.3109\/09537104.2010.513748","volume":"21","author":"N Schweinfurth","year":"2010","unstructured":"Schweinfurth, N., Hohmann, S., Deuschle, M., Lederbogen, F. & Schloss, P. Valproic acid and all trans retinoic acid differentially induce megakaryopoiesis and platelet-like particle formation from the megakaryoblastic cell line MEG-01. Platelets 21, 648\u2013657. https:\/\/doi.org\/10.3109\/09537104.2010.513748 (2010).","journal-title":"Platelets"},{"key":"97478_CR30","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1080\/09537104.2018.1528344","volume":"30","author":"A Dhenge","year":"2019","unstructured":"Dhenge, A., Kuhikar, R., Kale, V. & Limaye, L. Regulation of differentiation of MEG01 to megakaryocytes and platelet-like particles by Valproic acid through Notch3 mediated actin polymerization. Platelets 30, 780\u2013795. https:\/\/doi.org\/10.1080\/09537104.2018.1528344 (2019).","journal-title":"Platelets"},{"key":"97478_CR31","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1083\/jcb.201006102","volume":"191","author":"JN Thon","year":"2010","unstructured":"Thon, J. N. et al. Cytoskeletal mechanics of proplatelet maturation and platelet release. J. Cell Biol. 191, 861\u2013874. https:\/\/doi.org\/10.1083\/jcb.201006102 (2010).","journal-title":"J. Cell Biol."},{"key":"97478_CR32","doi-asserted-by":"publisher","first-page":"484","DOI":"10.3324\/haematol.2016.150375","volume":"102","author":"H Beauchemin","year":"2017","unstructured":"Beauchemin, H. et al. Gfi1b controls integrin signaling-dependent cytoskeleton dynamics and organization in megakaryocytes. Haematologica 102, 484\u2013497. https:\/\/doi.org\/10.3324\/haematol.2016.150375 (2017).","journal-title":"Haematologica"},{"key":"97478_CR33","doi-asserted-by":"publisher","first-page":"3178","DOI":"10.1182\/blood-2013-03-487942","volume":"122","author":"I Pleines","year":"2013","unstructured":"Pleines, I. et al. Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42. Blood 122, 3178\u20133187. https:\/\/doi.org\/10.1182\/blood-2013-03-487942 (2013).","journal-title":"Blood"},{"key":"97478_CR34","doi-asserted-by":"publisher","first-page":"3101","DOI":"10.1158\/0008-5472.CAN-18-0619","volume":"78","author":"MDM Maldonado","year":"2018","unstructured":"Maldonado, M. D. M. & Dharmawardhane, S. Targeting Rac and Cdc42 GTPases in Cancer. Cancer Res. 78, 3101\u20133111. https:\/\/doi.org\/10.1158\/0008-5472.CAN-18-0619 (2018).","journal-title":"Cancer Res."},{"key":"97478_CR35","doi-asserted-by":"publisher","first-page":"12445","DOI":"10.1074\/jbc.M600168200","volume":"281","author":"YK Peterson","year":"2006","unstructured":"Peterson, Y. K., Kelly, P., Weinbaum, C. A. & Casey, P. J. A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity. J. Biol. Chem. 281, 12445\u201312450. https:\/\/doi.org\/10.1074\/jbc.M600168200 (2006).","journal-title":"J. Biol. Chem."},{"key":"97478_CR36","doi-asserted-by":"publisher","first-page":"4418","DOI":"10.1038\/s41598-019-40988-7","volume":"9","author":"T Uehara","year":"2019","unstructured":"Uehara, T. et al. Pathogenetic basis of Takenouchi-Kosaki syndrome: Electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model. Sci. Rep. 9, 4418. https:\/\/doi.org\/10.1038\/s41598-019-40988-7 (2019).","journal-title":"Sci. Rep."},{"key":"97478_CR37","doi-asserted-by":"publisher","unstructured":"Gernez, Y. et al. Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1beta inhibition. J. Allergy Clin. Immunol. 144, 1122\u20131125 e1126. https:\/\/doi.org\/10.1016\/j.jaci.2019.06.017 (2019).","DOI":"10.1016\/j.jaci.2019.06.017"},{"key":"97478_CR38","doi-asserted-by":"publisher","first-page":"2995","DOI":"10.1182\/blood-2014-10-604504","volume":"125","author":"RE Kosoff","year":"2015","unstructured":"Kosoff, R. E. et al. Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization. Blood 125, 2995\u20133005. https:\/\/doi.org\/10.1182\/blood-2014-10-604504 (2015).","journal-title":"Blood"},{"key":"97478_CR39","doi-asserted-by":"publisher","first-page":"3137","DOI":"10.1182\/blood-2016-04-711630","volume":"128","author":"A Roy","year":"2016","unstructured":"Roy, A. et al. Activity of nonmuscle myosin II isoforms determines localization at the cleavage furrow of megakaryocytes. Blood 128, 3137\u20133145. https:\/\/doi.org\/10.1182\/blood-2016-04-711630 (2016).","journal-title":"Blood"},{"key":"97478_CR40","doi-asserted-by":"publisher","first-page":"4076","DOI":"10.1182\/blood-2005-06-2204","volume":"106","author":"SR Patel","year":"2005","unstructured":"Patel, S. R. et al. Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes. Blood 106, 4076\u20134085. https:\/\/doi.org\/10.1182\/blood-2005-06-2204 (2005).","journal-title":"Blood"},{"key":"97478_CR41","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s12915-018-0584-6","volume":"16","author":"J van Dijk","year":"2018","unstructured":"van Dijk, J. et al. Microtubule polyglutamylation and acetylation drive microtubule dynamics critical for platelet formation. BMC Biol. 16, 116. https:\/\/doi.org\/10.1186\/s12915-018-0584-6 (2018).","journal-title":"BMC Biol."},{"key":"97478_CR42","doi-asserted-by":"publisher","unstructured":"Strassel, C. et al. An essential role for alpha4A-tubulin in platelet biogenesis. Life Sci. Alliance. https:\/\/doi.org\/10.26508\/lsa.201900309 (2019).","DOI":"10.26508\/lsa.201900309"},{"key":"97478_CR43","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1182\/blood-2008-06-162610","volume":"113","author":"S Kunishima","year":"2009","unstructured":"Kunishima, S., Kobayashi, R., Itoh, T. J., Hamaguchi, M. & Saito, H. Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly. Blood 113, 458\u2013461. https:\/\/doi.org\/10.1182\/blood-2008-06-162610 (2009).","journal-title":"Blood"},{"key":"97478_CR44","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1080\/09537104.2017.1411587","volume":"29","author":"K Burley","year":"2018","unstructured":"Burley, K., Westbury, S. K. & Mumford, A. D. TUBB1 variants and human platelet traits. Platelets 29, 209\u2013211. https:\/\/doi.org\/10.1080\/09537104.2017.1411587 (2018).","journal-title":"Platelets"},{"key":"97478_CR45","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/s0092-8674(02)00800-0","volume":"109","author":"M Fukata","year":"2002","unstructured":"Fukata, M. et al. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 109, 873\u2013885. https:\/\/doi.org\/10.1016\/s0092-8674(02)00800-0 (2002).","journal-title":"Cell"},{"key":"97478_CR46","doi-asserted-by":"publisher","first-page":"26364","DOI":"10.1074\/jbc.M116.752121","volume":"291","author":"K Nouri","year":"2016","unstructured":"Nouri, K. et al. IQGAP1 interaction with RHO family proteins revisited: kinetic and equilibrium evidence for multiple Distinct Binding Sites. J. Biol. Chem. 291, 26364\u201326376. https:\/\/doi.org\/10.1074\/jbc.M116.752121 (2016).","journal-title":"J. Biol. Chem."},{"key":"97478_CR47","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.4103\/1673-5374.221148","volume":"12","author":"I Foldi","year":"2017","unstructured":"Foldi, I., Szikora, S. & Mihaly, J. Formin\u2019 bridges between microtubules and actin filaments in axonal growth cones. Neural Regen. Res. 12, 1971\u20131973. https:\/\/doi.org\/10.4103\/1673-5374.221148 (2017).","journal-title":"Neural Regen. Res."},{"key":"97478_CR48","doi-asserted-by":"publisher","first-page":"41749","DOI":"10.18632\/oncotarget.16978","volume":"8","author":"C Prunier","year":"2017","unstructured":"Prunier, C., Prudent, R., Kapur, R., Sadoul, K. & Lafanechere, L. LIM kinases: cofilin and beyond. Oncotarget 8, 41749\u201341763. https:\/\/doi.org\/10.18632\/oncotarget.16978 (2017).","journal-title":"Oncotarget"},{"key":"97478_CR49","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/79069","volume":"26","author":"MJ Kelley","year":"2000","unstructured":"Kelley, M. J., Jawien, W., Ortel, T. L. & Korczak, J. F. Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. Nat. Genet. 26, 106\u2013108. https:\/\/doi.org\/10.1038\/79069 (2000).","journal-title":"Nat. Genet."},{"key":"97478_CR50","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/79063","volume":"26","author":"M Seri","year":"2000","unstructured":"Seri, M. et al. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin\/Fechtner syndrome consortium. Nat. Genet. 26, 103\u2013105. https:\/\/doi.org\/10.1038\/79063 (2000).","journal-title":"Nat. Genet."},{"key":"97478_CR51","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1111\/jth.12436","volume":"11","author":"Y Chen","year":"2013","unstructured":"Chen, Y. et al. The abnormal proplatelet formation in MYH9-related macrothrombocytopenia results from an increased actomyosin contractility and is rescued by myosin IIA inhibition. J. Thrombosis Haemostasis JTH 11, 2163\u20132175. https:\/\/doi.org\/10.1111\/jth.12436 (2013).","journal-title":"J. Thrombosis Haemostasis JTH"},{"key":"97478_CR52","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1083\/jcb.147.4.831","volume":"147","author":"WB Kiosses","year":"1999","unstructured":"Kiosses, W. B., Daniels, R. H., Otey, C., Bokoch, G. M. & Schwartz, M. A. A role for p21-activated kinase in endothelial cell migration. J. Cell Biol. 147, 831\u2013844. https:\/\/doi.org\/10.1083\/jcb.147.4.831 (1999).","journal-title":"J. Cell Biol."},{"key":"97478_CR53","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1083\/jcb.145.4.837","volume":"145","author":"MA Sells","year":"1999","unstructured":"Sells, M. A., Boyd, J. T. & Chernoff, J. p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. J. Cell Biol. 145, 837\u2013849. https:\/\/doi.org\/10.1083\/jcb.145.4.837 (1999).","journal-title":"J. Cell Biol."},{"key":"97478_CR54","doi-asserted-by":"publisher","first-page":"5064","DOI":"10.1158\/1078-0432.CCR-15-0461","volume":"21","author":"Y Guo","year":"2015","unstructured":"Guo, Y. et al. A novel pharmacologic activity of ketorolac for therapeutic benefit in Ovarian cancer patients. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 21, 5064\u20135072. https:\/\/doi.org\/10.1158\/1078-0432.CCR-15-0461 (2015).","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97478-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97478-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97478-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T15:21:53Z","timestamp":1670080913000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97478-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["97478"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-97478-y","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]},"assertion":[{"value":"12 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17990"}}