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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 -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 -chain (eg, -GM-CSF receptor [ -GMR]) and a
common -subunit ( -GMR). Ligand binding is believed to induce assembly or conformational changes in preformed complexes containing more than one - and -subunit in the activated receptor complex. To analyze the function of a splice variant of -GMR with a
truncation in the intracellular domain ( -GMRIT), BaF-3
cells expressing human -GMR plus -GMR were transfected with
-GMRIT. In these cells, coexpression of
-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 -GMR sequences, -GMR and -GMRIT were coexpressed with different chimeric / -GMR constructs. Whereas both -GMR and -GMRIT generate high-affinity GMR
complexes in the presence of / -GMR, -GMRIT
inhibits while -GMR supports proliferation and cell survival
mediated by / -GMR. Correspondingly, -GMR, but not
-GMRIT, generates functional GMR complexes when coexpressed with a defective / -GMR construct. These data indicate that -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.

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