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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2689-2696

HEMATOPOIESIS

Inhibition of granulocyte-macrophage colony-stimulating factor receptor function by a splice variant of the common beta -receptor subunit

Katharina Wagner, Sabine Kafert-Kasting, Gerhard Heil, Arnold Ganser, and Matthias Eder

From the Department of Hematology and Oncology, Hannover Medical School, and the Center for Cell Therapy/Cytonet, Hannover, Germany.

The receptors for human granuloctye-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are composed of a ligand-specific alpha -chain (eg, alpha -GM-CSF receptor [alpha -GMR]) and a common beta -subunit (beta -GMR). Ligand binding is believed to induce assembly or conformational changes in preformed complexes containing more than one alpha - and beta -subunit in the activated receptor complex. To analyze the function of a splice variant of beta -GMR with a truncation in the intracellular domain (beta -GMRIT), BaF-3 cells expressing human alpha -GMR plus beta -GMR were transfected with beta -GMRIT. In these cells, coexpression of beta -GMRIT inhibits GM-CSF-mediated survival and proliferation in a GM-CSF concentration-dependent manner. To analyze the effect of cytoplasmic assembly of truncated and full-length intracellular beta -GMR sequences, beta -GMR and beta -GMRIT were coexpressed with different chimeric alpha /beta -GMR constructs. Whereas both beta -GMR and beta -GMRIT generate high-affinity GMR complexes in the presence of alpha /beta -GMR, beta -GMRIT inhibits while beta -GMR supports proliferation and cell survival mediated by alpha /beta -GMR. Correspondingly, beta -GMR, but not beta -GMRIT, generates functional GMR complexes when coexpressed with a defective alpha /beta -GMR construct. These data indicate that beta -GMRIT can inhibit survival and mitogenic signaling of the wild-type GMR and demonstrate that recruitment of alternatively spliced receptor subunits may regulate the function of heteromeric cytokine receptors.

© 2001 by The American Society of Hematology.
 

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