THE HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) RECEPTOR EXISTS AS A PREFORMED RECEPTOR COMPLEX THAT CAN BE ACTIVATED BY GM-CSF, INTERLEUKIN-3, OR INTERLEUKIN-5

The granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor is expressed on normal and malignant hematopoietic cells as well as o n cells from other organs in which it transduces a variety of function s. Despite the widespread expression and pleiotropic nature of the GM- CSF receptor, little is known about its assembly and activation mechan ism. Using a combination of biochemical and functional approaches, we have found that the human GM-CSF receptor exists as an inducible compl ex, analogous to the interleukin-3 (IL-3) receptor, and also as a pref ormed complex, unlike the IL-3 receptor or indeed other members of the cytokine receptor superfamily. We found that monoclonal antibodies to the GM-CSF receptor alpha chain (GMR alpha) and to the common beta ch ain of the GM-CSF, IL-3, and IL-5 receptors (beta(c)) immunoprecipitat ed both GMR alpha and beta(c) from the surface of primary myeloid cell s, myeloid cell lines, and transfected cells in the absence of GM-CSF. Further association of the two chains could be induced by the additio n of GM-CSF. The preformed complex required only the extracellular reg ions of GMR alpha and beta(c), as shown by the ability of soluble beta (c) to associate with membrane-anchored GMR alpha or soluble GMR alpha . Kinetic experiments on eosinophils and monocytes with radiolabeled G M-CSF, IL-3, and IL-5 showed association characteristics unique to GM- CSF. Significantly, receptor phosphorylation experiments showed that n ot only GM-CSF but also IL-3 and IL-5 stimulated the phosphorylation o f GMR alpha-associated beta(c). These results indicate a pattern of as sembly of the heterodimeric GM-CSF receptor that is unique among recep tors of the cytokine receptor superfamily. These results also suggest that the preformed GM-CSF receptor complex mediates the instantaneous binding of GM-CSF and is a target of phosphorylation by IL-3 and IL-5, raising the possibility that some of the biologic activities of IL-3 and IL-5 are mediated through the GM-CSF receptor complex. (C) 1997 by The American Society of Hematology.