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Volume 271, Number 26, Issue of June 28, 1996 pp. 15330-15335
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Ligand-independent Cell Surface Expression of the Human Soluble Granulocyte-Macrophage Colony-stimulating Factor Receptor  Subunit Depends on Co-expression of the Membrane-associated Receptor  Subunit

(Received for publication, November 17, 1995, and in revised form, March 21, 1996)

From the Department of Medicine, Cancer Biology Research Group, The University of Calgary, Calgary, Alberta, T2N 4N1 Canada

The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates its activity through binding to cell surface receptors. The receptor for GM-CSF belongs to a superfamily of cytokine receptors characterized by a conserved extracellular motif. The high affinity GM-CSF receptor (GMR) consists of two transmembrane anchored subunits; a ligand binding  subunit (transmembrane GMR) and a signal transducing  subunit (GMR), both of which belong to the cytokine receptor superfamily. The human GM-CSF receptor  subunit also exists in a soluble form (solGMR), which antagonizes GM-CSF activity in vitro. We directly tested the potential for solGMR to interact with GMR in vitro. Our experiments demonstrated that exogenous solGMR, even in the presence of GM-CSF, does not interact with GMR on the cell surface. However, when solGMR and GMR are co-expressed in baby hamster kidney cells, solGMR is retained on the cell surface and forms a functional intermediate affinity GM-CSF binding complex (K_d = 331 pM). In addition, the cell surface expression of solGMR is independent of the presence of GM-CSF as demonstrated using flow cytometry. Cells expressing only solGMR do not show cell surface retention or form functional GM-CSF cell surface binding complexes. Sequencing of our GMR clone revealed a nucleotide substitution (A  C) resulting in the substitution of Ala for Glu at position 9 from the amino terminus of the mature GMR peptide. Because the GMR (A  C) clone is capable of forming functional high affinity receptors with transmembrane GMR (K_d = 64 pM), we feel that the cell surface retention of solGMR is independent of the GMR mutation. We suggest that the co-expression and interaction of solGMR and GMR represents a previously unrecognized GM-CSF receptor complex and a novel, ligand-independent mechanism of cytokine receptor assembly.

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