Recombinant Human Thrombopoietin/TPO

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].

Reference

[1]. Deutsch, V.R. and A. Tomer (2006) Br. J. Haematol. 134:453.

[2]. Kaushansky, K. (2005) J. Clin. Invest. 115:3339.

[3]. Li, J. et al. (1999) Br. J. Haematol. 106:345.

[4]. Bartley, T.D. et al. (1994) Cell 77:1117.

[5]. de Sauvage, F.J. et al. (1994) Nature 369:533.

[6]. Marcucci, R. and M. Romano (2008) Biochim. Biophys. Acta 1782:427.

[7]. Kaushansky, K. et al. (1994) Nature 369:568.

[8]. Kaushansky, K. et al. (1995) Proc. Natl. Acad. Sci. 92:3234.

[9]. Broudy, V.C. et al. (1995), Blood 85:1719.

[10]. Lok, S.I. et al. (1994) Nature 369:565.

[11]. Chen, J. et al. (1995) Blood 86:4054.

[12]. Oda, A. et al. (1996) Blood 87:4664.

[13]. Van Os, E. et al. (2003) Br. J. Haematol. 121:482.

[14]. Kato, T. et al. (1997) Proc. Natl. Acad. Sci. 94:4669.