Thrombopoietin (TPO) is the primary regulator of thrombopoiesis. Through its interaction with the c-Mpl receptor, TPO initiates a signaling cascade by triggering the phosphorylation and activation of Jak2. Although this is well established, it remains unclear as to how TPO signaling is modulated, which has important consequences for the regulation of cell growth and differentiation. Dysregulation of TPO signaling, as exemplified by mutations conferring constitutive activity to Jak2 or c-Mpl, is known to underlie the development of congenital and acquired myeloproliferative disorders (MPDs), including polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). In addition, TPO-mimetics are emerging as important tools for the treatment of patients with thrombocytopenia of both benign and neoplastic etiologies. In this competitive renewal we propose to study the regulation of TPO signaling, including: 1) c-Mpl receptor trafficking and internalization in response to TPO, 2) regulation of c-Mpl degradation and its consequences for TPO signaling, and 3) functional similarities and differences between TPO and erythropoietin (EPO) signaling.
In this renewal of "The molecular and cellular biology of thrombopoeitin" we propose to build on our previous work on the mechanisms of thrombopoietin signaling. In particular we will study the physiology of c-Mpl receptor trafficking, pathways that regulate degradation of c-Mpl, and functional similarities and differences between Thrombopoietin and erythropoietin signaling. The results of these studies will provide new insights into the role of thrombopoietin signaling in normal as well as malignant cells.
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|Etheridge, S Leah; Roh, Michelle E; Cosgrove, Megan E et al. (2014) JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms. Proc Natl Acad Sci U S A 111:2295-300|
|Jung, Andre Scott; Kaushansky, Alexis; Macbeath, Gavin et al. (2011) Tensin2 is a novel mediator in thrombopoietin (TPO)-induced cellular proliferation by promoting Akt signaling. Cell Cycle 10:1838-44|
|Saur, Sebastian J; Sangkhae, Veena; Geddis, Amy E et al. (2010) Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood 115:1254-63|
|Fox, Norma E; Lim, Jihyang; Chen, Rose et al. (2010) F104S c-Mpl responds to a transmembrane domain-binding thrombopoietin receptor agonist: proof of concept that selected receptor mutations in congenital amegakaryocytic thrombocytopenia can be stimulated with alternative thrombopoietic agents. Exp Hematol 38:384-91|
|Geddis, Amy E (2010) Megakaryopoiesis. Semin Hematol 47:212-9|
|Kaushansky, Kenneth; Ranney, Helen M (2009) Thrombopoietin in normal and neoplastic stem cell development. Best Pract Res Clin Haematol 22:495-9|
|Geddis, Amy E (2009) Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Hematol Oncol Clin North Am 23:321-31|
|Fox, Norma E; Chen, Rose; Hitchcock, Ian et al. (2009) Compound heterozygous c-Mpl mutations in a child with congenital amegakaryocytic thrombocytopenia: functional characterization and a review of the literature. Exp Hematol 37:495-503|
|Hitchcock, Ian S; Chen, Maximus M; King, Jennifer R et al. (2008) YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation. Blood 112:2222-31|
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