GMP Human Thrombopoietin Protein

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) . Both full length Tpo and shorter forms circulate in the plasma, with the shorter, N‑terminal EPO-like domain forms showing significantly increased specific activity (4, 5, 15) . The C‑terminal domain is not required for binding to Tpo R or inducing MK growth and differentiation (5) . Aside from its hematopoietic effects, Tpo is expressed in the brain where it promotes the apoptosis of hypoxia-sensitized neurons and inhibits neuronal differentiation by blocking NGF induced signaling (16, 17) .