Journal of Biological Chemistry
Volume 281, Issue 31, 4 August 2006, Pages 22421-22426
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Mechanisms of Signal Transduction
The α Subunit of the Granulocyte-Macrophage Colony-stimulating Factor Receptor Interacts with c-Kit and Inhibits c-Kit Signaling*

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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.

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This work was supported by grants from the National Institutes of Health (CA30388), the New York State Department of Health, and the Lebensfeld and Schultz Foundations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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