Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease

Behrens, K; Kauppi, M; Viney, EM; Kueh, AJ; Hyland, CD; Willson, TA; Salleh, L; de Graaf, CA; Babon, JJ; Herold, MJ; Nicola, NA; Alexander, WS

Author(s): Behrens, K; Kauppi, M; Viney, EM; Kueh, AJ; Hyland, CD; Willson, TA; Salleh, L; de Graaf, CA; Babon, JJ; Herold, MJ; Nicola, NA; Alexander, WS;
Details: Publication Year 2024-03-15,Volume 38,Issue #6,Page 1342-1352
Journal Title: Leukemia
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 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.
Publisher: Springer Nature
Keywords: Animals; *Receptors, Thrombopoietin/metabolism/genetics; *Myeloproliferative Disorders/genetics/metabolism/pathology; Mice; *Hematopoiesis; *Thrombopoietin/metabolism; *Tyrosine/metabolism/genetics; Phosphorylation; Mice, Inbred C57BL; Hematopoietic Stem Cells/metabolism; Signal Transduction; Mutation; Janus Kinase 2/genetics/metabolism; Thrombopoiesis/genetics
Research Division(s): Structural Biology; Blood Cells And Blood Cancer; Structural Biology
PubMed ID: 38491305
Publisher's Version: https://doi.org/10.1038/s41375-024-02219-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41375-024-02219-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41375-024-02219-5.pdf - (3.79MB, application/pdf)

Creation Date: 2024-03-18 02:11:28

Last Modified: 2024-08-23 03:15:33