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Cloettapreis_2004_Nr_32

Since mice deficient for mpl are viable, they can be used as a genetic background to introduce mutant receptors and assess their capability to complement the platelet deficiency in vivo. We have introduced trans- genes encoding c-mpl mutants into c-mpl-deficient mice and found that these mutants change platelet levels, but not platelet function or the balance between cells of different hematopoietic lineages (Coers et al., in preparation). These results are again consistent with the predictions of the permissive model. Recently, we have studied the function of a truncated mpl receptor iso- form (mpl-tr), which results from alternative splicing (Skoda et al., 1993). The mpl-tr variant is the only alternate mpl isoform conserved between mouse and humans, suggesting a relevant function in regulat- ing mpl signaling. Despite the presence of a signal peptide and the lack of a transmembrane domain, mpl-tr is retained intracellularly. Our results provide evidence that mpl-tr exerts a dominant-negative effect on thrombopoietin-dependent cell proliferation and survival (Coers et al., 2004). We demonstrated that this inhibitory effect is due to down- regulation of the full-length mpl protein. The C terminus of mpl-tr, consisting of 30 amino acids of unique sequence, is essential for the suppression of TPO-dependent proliferation and mpl protein down- regulation. Cathepsin inhibitor-1 (CATI-1), an inhibitor of cathepsin- like cysteine proteases, counteracts the effect of mpl-tr on mpl protein expression, suggesting that mpl-tr targets mpl for lysosomal degrada- tion. Together, these data suggest a new paradigm for the regulation of cytokine receptor expression and function through a proteolytic process directed by a truncated isoform of the same receptor. This example highlights the many levels of fine-tuning nature invented to obtain a robust regulatory system for maintaining stable numbers of circulating blood cells. Aberrant megakaryopoiesis in hereditary forms of myeloproliferative disorders. Myeloproliferative disorders (MPD) are a heterogeneous group of diseases characterized by increased hematopoiesis leading to elevated 44

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