{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:27:14Z","timestamp":1791487634333,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["287512"],"award-info":[{"award-number":["287512"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP\u2010111138"],"award-info":[{"award-number":["MOP\u2010111138"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>KIT, a type III tyrosine kinase receptor, plays a crucial role in haematopoietic development. The KIT receptor forms a dimer after ligand binding; this activates tyrosine kinase activity leading to downstream signal transduction. The D816V KIT mutation is extensively implicated in haematological malignancies, including mastocytosis and leukaemia. KIT D816V is constitutively active, but the molecular nuances that lead to constitutive tyrosine kinase activity are unclear. For the first time, we present experimental evidence that the KIT D816V mutant does not dimerize like KIT wild type. We further show evidence of decreased stabilization of the tyrosine kinase domain in the KIT D816V mutant, a phenomenon that might contribute to its constitutive activity. Since the mechanism of KIT D816V activation varies from that of the wild type, we explored downstream signal transduction events and found that even though KIT D816V targets similar signalling moieties, the signalling is amplified in the mutant compared to stem cell factor\u2010activated wild type receptor. Uniquely, KIT D816V induces infection\u2010related pathways and the spliceosome pathway, providing alternate options for selective as well as combinatorial therapeutic targeting.<\/jats:p>","DOI":"10.1111\/bjh.18116","type":"journal-article","created":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T13:26:54Z","timestamp":1646400414000},"page":"960-970","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<scp>KIT D816V<\/scp>\n                    is dimerization\u2010independent and activates downstream pathways frequently perturbed in mastocytosis"],"prefix":"10.1111","volume":"202","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3323-181X","authenticated-orcid":false,"given":"Vinothkumar","family":"Rajan","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Dalhousie University  Halifax NS Canada"},{"name":"Biological Sciences Platform Sunnybrook Research Institute  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey V.","family":"Prykhozhij","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario (CHEO) Research Institute and University of Ottawa  Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya","family":"Pandey","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology Dalhousie University  Halifax NS Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro M.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology Dalhousie University  Halifax NS Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan K.","family":"Rainey","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology Dalhousie University  Halifax NS Canada"},{"name":"Department of Chemistry Dalhousie University  Halifax NS Canada"},{"name":"School of Biomedical Engineering Dalhousie University  Halifax NS Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4053-6067","authenticated-orcid":false,"given":"Jason N.","family":"Berman","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario (CHEO) Research Institute and University of Ottawa  Ottawa ON Canada"},{"name":"Department of Pediatrics University of Ottawa  Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.10.6311"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.12.6895"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(99)00078-3"},{"key":"e_1_2_8_5_1","first-page":"1979","article-title":"Signaling via Src family kinases is required for normal internalization of the receptor c\u2010Kit","volume":"94","author":"Broudy VC","year":"1999","journal-title":"Blood"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.48.30519"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205559"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.05.055"},{"key":"e_1_2_8_9_1","first-page":"639","article-title":"Structural insights into the conformational selectivity of STI\u2010571 and related kinase inhibitors","volume":"7","author":"Mol C","year":"2004","journal-title":"Curr Opin Drug Discov Devel"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03033708"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02557518"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2003.04362.x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V78.11.2962.2962"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.2.701"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2009.281"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-04-015545"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.4.1609"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.5.1741"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5486.1938"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-10-3969"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01539-8"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01153-06"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.3.790.bloodjournal853790"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00046.2011"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002068"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21029"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079666"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403319200"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1017\/S003358359800345X"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560060218"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molliq.2017.01.018"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.284"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.095133"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/151839"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2014.09.001"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-06-359984"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1513098"},{"key":"e_1_2_8_39_1","first-page":"2609","article-title":"Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF\u2010binding proteins","volume":"118","author":"Guix M","year":"2008","journal-title":"J Clin Invest"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-131559"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.18116","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bjh.18116","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.18116","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T21:12:18Z","timestamp":1697404338000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.18116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,4]]},"references-count":39,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1111\/bjh.18116"],"URL":"https:\/\/doi.org\/10.1111\/bjh.18116","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,4]]},"assertion":[{"value":"2021-12-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}