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Prepublished online as a Blood First Edition Paper on March 6, 2003; DOI 10.1182/blood-2002-11-3468.
Submitted November 15, 2002
Accepted February 6, 2003
Internalization of the thrombopoietin receptor is regulated by two cytoplasmic motifs
Debra D Dahlen*, Virginia C Broudy, and Jonathan G Drachman
Division of Hematology, University of Washington, Seattle, WA, USA
Puget Sound Blood Center and Program, Seattle, WA, USA
* Corresponding author; email: debrad{at}u.washington.edu.
Receptor-mediated internalization appears to be the primary means of regulating the plasma level of thrombopoietin (TPO). However, the processes that regulate Mpl internalization have not previously been described. Using the cytokine-dependent cell line BaF3, we have identified two distinct motifs within the cytoplasmic domain of Mpl that underlie ligand-dependent internalization. Removal of the fourth cytoplasmic tyrosine residue by deletion or truncation results in a significant decrease in maximal internalization. The remaining receptor internalization is abrogated by deletion of cytoplasmic residues 54-69, which includes the core box2 region (L54L55E56I57L58) and the only dileucine motifs (L54L55 and I57L58) within the cytoplasmic domain of Mpl. Receptor internalization mediated by this latter subdomain does not require Jak2 activation. Furthermore, TPO-stimulated cellular proliferation appears to be directly correlated with receptor internalization, indicating that internalization of the TPO/Mpl complex may be essential for normal signal transduction. Finally, we have demonstrated that upon removal of TPO from the supernatant, Mpl promptly reappears on the cell surface, suggesting that a pool of intracellular Mpl can be rapidly recycled to the cell surface. These data help identify the receptor motifs involved in TPO-induced internalization of Mpl and suggest that Mpl translocation may be necessary for normal cellular proliferation.
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