Thrombopoietin (Tpo), is a key regulator of megakaryocytopoiesis and thrombopoiesis. It is principally produced in the liver and is bound and internalized by the receptor Tpo R/c-mpl. Defects in the Tpo-Tpo R signaling pathway are associated with a variety of platelet disorders [1-3]. The 353 amino acid (aa) human Tpo precursor is cleaved to yield the 332 aa mature protein. Mature human Tpo shares approximately 70% aa sequence homology with mouse and rat Tpo. It is an 80-85 kDa protein that consists of an N-terminal domain with homology to Erythropoietin (Epo) and a C-terminal domain that contains multiple N-linked and O-linked glycosylation sites [4, 5]. Tissue specific alternate splicing of human Tpo generates multiple isoforms with internal deletions, insertions, and/or C-terminal substitutions [6]. Tpo promotes the differentiation, proliferation, and maturation of MK and their progenitors [4, 5, 7]. Several other cytokines can promote these functions as well but only in cooperation with Tpo [8, 9]. Notably, IL-3 independently induces MK development, although its effects are restricted to early in the MK lineage [8, 9]. Tpo additionally promotes platelet production, aggregation, ECM adhesion, and activation [10, 13]. It is cleaved by platelet-derived thrombin following Arg191 within the C-terminal domain and subsequently at other sites upon extended digestion [14]. Full length Tpo and shorter forms circulate in the plasma [4, 5]. The C-terminal domain is not required for binding to Tpo R or inducing MK growth and differentiation [5].
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