Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/9302
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Type: Journal article
Title: Molecular assembly of the ternary granulocyte-macrophage colony-stimulating factor receptor complex
Author: Mc Clure, B.
Hercus, T.
Cambareri, B.
Woodcock, J.
Bagley, C.
Howlett, G.
Lopez, A.
Citation: Blood, 2003; 101(4):1308-1315
Publisher: Amer Soc Hematology
Issue Date: 2003
ISSN: 0006-4971
1528-0020
Statement of
Responsibility: 
Mcclure, Barbara J ; Hercus, Timothy R ; Cambareri, Bronwyn A ; Woodcock, Joanna M ; Bagley, Christopher J ; Howlett, Geoff J ; Lopez, Angel F
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that stimulates the production and functional activity of granulocytes and macrophages, properties that have encouraged its clinical use in bone marrow transplantation and in certain infectious diseases. Despite the importance of GM-CSF in regulating myeloid cell numbers and function, little is known about the exact composition and mechanism of assembly of the GM-CSF receptor complex. We have now produced soluble forms of the GM-CSF receptor alpha chain (sGMRalpha) and beta chain (sbetac) and utilized GM-CSF, the GM-CSF antagonist E21R (Glu21Arg), and the betac-blocking monoclonal antibody BION-1 to define the molecular assembly of the GM-CSF receptor complex. We found that GM-CSF and E21R were able to form low-affinity, binary complexes with sGMRalpha, each having a stoichiometry of 1:1. Importantly, GM-CSF but not E21R formed a ternary complex with sGMRalpha and sbetac, and this complex could be disrupted by E21R. Significantly, size-exclusion chromatography, analytical ultracentrifugation, and radioactive tracer experiments indicated that the ternary complex is composed of one sbetac dimer with a single molecule each of sGMRalpha and of GM-CSF. In addition, a hitherto unrecognized direct interaction between betac and GM-CSF was detected that was absent with E21R and was abolished by BION-1. These results demonstrate a novel mechanism of cytokine receptor assembly likely to apply also to interleukin-3 (IL-3) and IL-5 and have implications for our molecular understanding and potential manipulation of GM-CSF activation of its receptor.
Keywords: Animals; Humans; Spodoptera; Baculoviridae; Phosphorus Radioisotopes; Granulocyte-Macrophage Colony-Stimulating Factor; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Recombinant Proteins; DNA, Complementary; Ultracentrifugation; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Spectrometry, Mass, Electrospray Ionization; Cloning, Molecular; Transfection; Polymerase Chain Reaction; Isotope Labeling; Binding Sites; Molecular Structure; Dimerization; Solubility
RMID: 0020031298
DOI: 10.1182/blood-2002-06-1903
Appears in Collections:Medicine publications

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