THE GAMMA-SUBUNIT OF THE HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR-RECEPTOR SIGNALS FOR GLUCOSE-TRANSPORT VIA A PHOSPHORYLATION-INDEPENDENT PATHWAY

The receptor for granulocyte-macrophage colony-stimulating factor (GM- CSF) is composed of an alpha and beta subunit, which together form the high-affinity receptor. The alpha subunit by itself binds ligand at l ow affinity, whereas the isolated beta subunit does not bind GM-CSF. I t is generally believed that the high-affinity receptor is responsible for the multiple functions of GM-CSF and that the isolated alpha subu nit (GMRalpha) does not transduce a signal. Xenopus laevis oocytes inj ected with RNA encoding human GMRalpha expressed up to 10(10) low-affi nity sites for GM-CSF (K(d) = 6 nM). GM-CSF binding to the alpha subun it expressed in Xenopus oocytes caused activation of 2-deoxyglucose tr ansport through endogenous glucose transporters. 2-Deoxyglucose transp ort was stimulated by similar low concentrations of GM-CSF in HL-60 le ukemia cells as well as normal human neutrophils and Xenopus oocytes e xpressing GMRalpha. Engagement of the isolated alpha subunit in oocyte s did not lead to protein phosphorylation or tyrosine phosphorylation of mitogen-activated protein kinase (MAP kinase). Staurosporin and gen istein inhibited GM-CSF-induced tyrosine phosphorylation of MAP kinase in human neutrophils and HL-60 cells without affecting GM-CSF-stimula ted uptake of 2-deoxyglucose. These results provide direct evidence th at the isolated alpha subunit signals for hexose transport and can do so without engagement of the kinase cascade. Our data also indicate th at signaling for hexose uptake may occur in a phosphorylation-independ ent manner in cells expressing the high-affinity GM-CSF receptor.