A CRITICAL ROLE FOR THE CYTOPLASMIC DOMAIN OF THE GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR ALPHA-RECEPTOR IN MEDIATING CELL-GROWTH

The human granulocyte-macrophage colony-stimulating factor (GM-CSF) re ceptor is composed of an alpha subunit which binds GM-CSF and a beta s ubunit which allows for high affinity binding. To investigate the role of the short cytoplasmic tail (54 amino acids) of the a receptor in m ediating signal transduction and in controlling cell growth, we placed a stop codon after the a receptor transmembrane domain and expressed this receptor in murine Ba/F3 cells. Unlike the complete alpha subunit , this shortened receptor was unable to stimulate protein phosphorylat ion or mediate entry into the cell cycle. By comparing Ba/F3 cells exp ressing the alpha and beta receptors with those expressing the alpha o r the terminated alpha receptor, we have been able to correlate specif ic GM-CSF-induced events with cell cycle commitment. We find that cell growth is correlated with prolonged increases in the cell levels of c -myc, pim-1, and cyclin D2 mRNAs, but not with changes in either immed iate early genes or mitogen-activated protein kinase phosphorylation. This suggests that additional signal transduction pathways not mediate d by known phosphoproteins are activated by GM-CSF. Since the beta rec eptor is shared by human interleukins 3 and 5, our data suggest that t he specificity of response to GM-CSF is mediated in part by the short cytoplasmic tail of the a receptor subunit.