دورية أكاديمية
Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease.
| العنوان: | Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease. |
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| المؤلفون: | Behrens K; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. behrens.k@wehi.edu.au.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. behrens.k@wehi.edu.au., Kauppi M; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia., Viney EM; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Kueh AJ; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., Hyland CD; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Willson TA; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia., Salleh L; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., de Graaf CA; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia., Babon JJ; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia., Herold MJ; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., Nicola NA; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia., Alexander WS; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. |
| المصدر: | Leukemia [Leukemia] 2024 Jun; Vol. 38 (6), pp. 1342-1352. Date of Electronic Publication: 2024 Mar 15. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2000- : London : Nature Publishing Group, Specialist Journals Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987- |
| مواضيع طبية MeSH: | Receptors, Thrombopoietin*/metabolism , Receptors, Thrombopoietin*/genetics , Myeloproliferative Disorders*/genetics , Myeloproliferative Disorders*/metabolism , Myeloproliferative Disorders*/pathology , Hematopoiesis* , Thrombopoietin*/metabolism , Tyrosine*/metabolism , Tyrosine*/genetics, Animals ; Mice ; Phosphorylation ; Mice, Inbred C57BL ; Hematopoietic Stem Cells/metabolism ; Signal Transduction ; Mutation ; Janus Kinase 2/genetics ; Janus Kinase 2/metabolism ; Thrombopoiesis/genetics |
| مستخلص: | Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo binding to Mpl triggers activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellular responses. Three tyrosine (Y) residues in the C-terminal region of the Mpl intracellular domain have been implicated as sites of phosphorylation required for regulation of major Tpo-stimulated signalling pathways: Mpl-Y565, Mpl-Y599 and Mpl-Y604. Here, we have introduced mutations in the mouse germline and report a consistent physiological requirement for Mpl-Y599, mutation of which resulted in thrombocytopenia, deficient megakaryopoiesis, low hematopoietic stem cell (HSC) number and function, and attenuated responses to myelosuppression. We further show that in models of myeloproliferative neoplasms (MPN), where Mpl is required for pathogenesis, thrombocytosis was dependent on intact Mpl-Y599. In contrast, Mpl-Y565 was required for negative regulation of Tpo responses; mutation of this residue resulted in excess megakaryopoiesis at steady-state and in response to myelosuppression, and exacerbated thrombocytosis associated with MPN. (© 2024. The Author(s).) |
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| معلومات مُعتمدة: | 341020624 Deutsche Forschungsgemeinschaft (German Research Foundation); 1121755 Department of Health | National Health and Medical Research Council (NHMRC); 1122999 Department of Health | National Health and Medical Research Council (NHMRC); 1113577 Department of Health | National Health and Medical Research Council (NHMRC); 1156095 Department of Health | National Health and Medical Research Council (NHMRC); 1159658 Department of Health | National Health and Medical Research Council (NHMRC); 1145728 Department of Health | National Health and Medical Research Council (NHMRC); 1173342 Department of Health | National Health and Medical Research Council (NHMRC); 1147328 Cancer Council Victoria |
| المشرفين على المادة: | 0 (Receptors, Thrombopoietin) 0 (Mpl protein, mouse) 9014-42-0 (Thrombopoietin) 42HK56048U (Tyrosine) EC 2.7.10.2 (Janus Kinase 2) |
| تواريخ الأحداث: | Date Created: 20240316 Date Completed: 20240603 Latest Revision: 20240627 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC11147766 |
| DOI: | 10.1038/s41375-024-02219-5 |
| PMID: | 38491305 |
| قاعدة البيانات: | MEDLINE |
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| DOI: | 10.1038/s41375-024-02219-5 |