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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 365-367
Deletion of the Extracellular Membrane-Distal Cytokine Receptor
Homology Module of Mpl Results in Constitutive Cell Growth and Loss
of Thrombopoietin Binding
Diana F. Sabath,
Kenneth Kaushansky, and
Virginia C. Broudy
From the Department of Medicine, University of
Washington, Seattle, WA.
The thrombopoietin receptor, Mpl, is a member of the cytokine
receptor superfamily. The extracellular domain of Mpl contains two
copies of the cytokine receptor homology module (CRM). Mpl is encoded
by c-mpl, the cellular homologue of the oncogene v-mpl. The oncogenic potential of v-mpl may arise from deletion of all but the 43 most membrane-proximal amino acids of the extracellular domain of the wild-type receptor. To test the hypothesis that the
extracellular domain of Mpl plays a role in controlling receptor activity, we created mutants of murine Mpl in which the membrane-distal CRM was either deleted or replaced by the membrane-proximal CRM. Introduction of these mutant receptors into factor-dependent BaF3 cells
led to constitutive cell growth in the absence of growth factor. Both
mutant receptors failed to bind 125I-Tpo. These results
suggest that the membrane-distal CRM of Mpl acts as a brake on cell
proliferation and that this region is required for ligand binding.
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