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J. Biol. Chem., Vol. 281, Issue 31, 22421-22426, August 4, 2006

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

Jian Chen¹, Juan M. Cárcamo², and David W. Golde

From the Department of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021 and the Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

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 (GMR) and (GMR) 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 GMR directly interacts with c-Kit and that the interaction is mediated by the cytoplasmic domains. Furthermore, GMR inhibited c-Kit auto-phosphorylation induced by the ligand stem cell factor. Consistent with the inhibitory effect, the expression of GMR was suppressed in cells whose viability was dependent on c-Kit signaling. In contrast, the alternatively spliced 2 isoform of the GMR could not inhibit c-Kit signaling, providing a rationale for the existence of the 2 isoform. Our results suggest that in addition to having the commonly appreciated roles in cytokine signal transduction, the receptors GMR and c-Kit could interact to coordinate their signal initiation.

Received for publication, May 15, 2006

^* 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.

Deceased August 9, 2004.

¹ To whom correspondence may be addressed. E-mail: jchen10021{at}yahoo.com.

² To whom correspondence may be addressed. Tel.: 917-575-8593; Fax: 212-849-2525; E-mail: jcarcamo{at}enzobio.com.

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