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-TpoR signaling pathway are associated with a variety of platelet disorders . 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 ratTpo. 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 andO-linked glycosylation sites. Tissue specific alternate splicing of human Tpo generates multiple isoforms with internal deletions, insertions, and/or C-terminal substitutions.Tpo promotes the differentiation, proliferation, and maturation of MK and their progenitors. Several other cytokines can promote these functions as well but only in cooperation with Tpo. Notably, IL-3 independently induces MK development, although its effects are restricted to early in the MK lineage .Tpo additionally promotes platelet production, aggregation,ECM adhesion, and activation. It is cleaved by platelet-derived thrombin following Arg191 within the C-terminal domain and subsequently at other sites upon extended digestion . Full length Tpo and shorter forms circulate in the plasma. The C-terminal domain is not required for binding toTpoR or inducing MK growth and differentiation.
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