The α Subunit of the Granulocyte-Macrophage Colony-stimulating Factor Receptor Interacts with c-Kit and Inhibits c-Kit Signaling

The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates hematopoiesis and the function of mature host defense cells through the GM-CSF receptor (GMR), which is composed of α (αGMR) and β (βGMR) subunits. Stem cell factor is another important hematopoietic cytokine that signals through c-Kit, a receptor tyrosine kinase, and regulates hematopoietic stem cell maintenance and erythroid development. Like other cytokine receptors, GMR and c-Kit are generally deemed as independent adaptor molecules capable of transducing cytokine-specific signals. We found that the αGMR directly interacts with c-Kit and that the interaction is mediated by the cytoplasmic domains. Furthermore, αGMR inhibited c-Kit auto-phosphorylation induced by the ligand stem cell factor. Consistent with the inhibitory effect, the expression of αGMR was suppressed in cells whose viability was dependent on c-Kit signaling. In contrast, the alternatively spliced α2 isoform of the αGMR could not inhibit c-Kit signaling, providing a rationale for the existence of the α2 isoform. Our results suggest that in addition to having the commonly appreciated roles in cytokine signal transduction, the receptors αGMR and c-Kit could interact to coordinate their signal initiation.