Journal article
Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease
K Behrens, M Kauppi, EM Viney, AJ Kueh, CD Hyland, TA Willson, L Salleh, CA de Graaf, JJ Babon, MJ Herold, NA Nicola, WS Alexander
Leukemia | SPRINGERNATURE | Published : 2024
Abstract
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 requir..
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Awarded by Australian Government
Funding Acknowledgements
We thank Doug Hilton for insightful comments and suggestions, Janelle Lochland and Ladina Di Rago for skilled assistance and the WEHI Bioservices, Histology and Flow Cytometry Laboratories for assistance. This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF). This work was supported by the Australian National Health and Medical Research Council (NHMRC) (Project Grants 1122999, 1159658, 1186575 and 1145728, program grant 1113577, Fellowship 1156095 to MJH, Fellowship 1121755 to JJB, Investigator grant 1173342 to WSA and Independent Research Institutes Infrastructure Support Scheme grants), the Cancer Council of Victoria (project grant 1147328 and 2021 Grant In Aid to MJH), the Medical Research Future Fund (grant MRF2008972) the Australian Cancer Research Fund, and the Victorian State Government Operational Infrastructure Support scheme. KB received a fellowship (341020624) from the Deutsche Forschungsgemeinschaft. The generation of CRISPR/Cas9 modified mice used in this study was supported by Phenomics Australia and the Australian Government through the National Collaborative Research Infrastructure Strategy program.