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We propose and document a new mechanism in which elevated tyrosine phosphorylation of Band 3 initiates sequelae that cause vaso\u2010occlusion and the symptoms of SCD. In this mechanism, denaturation of HbS and release of heme generate intracellular oxidants which cause inhibition of erythrocyte tyrosine phosphatases, thus permitting constitutive tyrosine phosphorylation of Band 3. This phosphorylation in turn induces dissociation of the spectrin\u2010actin cytoskeleton from the membrane, leading to membrane weakening, discharge of membrane\u2010derived microparticles (which initiate the coagulation cascade) and release of cell\u2010free HbS (which consumes nitric oxide) and activates the endothelium to express adhesion receptors). These processes promote vaso\u2010occlusive events which cause SCD. We further show that inhibitors of Syk tyrosine kinase block Band 3 tyrosine phosphorylation, prevent release of cell\u2010free Hb, inhibit discharge of membrane\u2010derived microparticles, increase sickle cell deformability, reduce sickle cell adhesion to human endothelial cells, and enhance sickle cell flow through microcapillaries. In view of reports that imatinib (a Syk inhibitor) successfully treats symptoms of sickle cell disease, we suggest that Syk tyrosine kinase inhibitors warrant repurposing as potential treatments for SCD.<\/jats:p>","DOI":"10.1111\/bjh.16671","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T05:35:03Z","timestamp":1588138503000},"page":"599-609","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease"],"prefix":"10.1111","volume":"190","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7696-4488","authenticated-orcid":false,"given":"Panae","family":"Noomuna","sequence":"first","affiliation":[{"name":"Department of Chemistry Purdue University West Lafayette IN USA"},{"name":"Institute for Drug Discovery Purdue University West Lafayette IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Risinger","sequence":"additional","affiliation":[{"name":"College of Nursing University of Cincinnati Cincinnati OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering University of California Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Seu","sequence":"additional","affiliation":[{"name":"Cancer and Blood Diseases Institute Cincinnati Children's Hospital Medical Center Cincinnati OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuncheng","family":"Man","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Case Western Reserve University Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"An","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Case Western Reserve University Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Sheik","sequence":"additional","affiliation":[{"name":"Department of Chemistry Purdue University West Lafayette IN USA"},{"name":"Institute for Drug Discovery Purdue University West Lafayette IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiandi","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering University of California Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"Little","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Hematology\/Oncology and UNC Blood Research Center University of North Carolina Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umut A.","family":"Gurkan","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Case Western Reserve University Cleveland OH USA"},{"name":"Department of Biomedical Engineering Case Western Reserve University Cleveland OH USA"},{"name":"Department of Orthopaedics Case Western Reserve University Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco M.","family":"Turrini","sequence":"additional","affiliation":[{"name":"Department of Genetics, Biology and Biochemistry University of Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodosia","family":"Kalfa","sequence":"additional","affiliation":[{"name":"Cancer and Blood Diseases Institute Cincinnati Children's Hospital Medical Center Cincinnati OH USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Low","sequence":"additional","affiliation":[{"name":"Department of Chemistry Purdue University West Lafayette IN USA"},{"name":"Institute for Drug Discovery Purdue University West Lafayette IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-018-0003-2"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2015.08.005"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","unstructured":"BallasSK MohandasN. 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