The alpha 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 alpha (alphaGMR) and beta (betaGMR) 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 alphaGMR directly interacts with c-Kit and that the interaction is mediated by the cytoplasmic domains. Furthermore, alphaGMR inhibited c-Kit auto-phosphorylation induced by the ligand stem cell factor. Consistent with the inhibitory effect, the expression of alphaGMR was suppressed in cells whose viability was dependent on c-Kit signaling. In contrast, the alternatively spliced alpha2 isoform of the alphaGMR could not inhibit c-Kit signaling, providing a rationale for the existence of the alpha2 isoform. Our results suggest that in addition to having the commonly appreciated roles in cytokine signal transduction, the receptors alphaGMR and c-Kit could interact to coordinate their signal initiation.
Chen
Jian
J
Department of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021; Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021. Electronic address: jchen10021@yahoo.com.
Cárcamo
Juan M
JM
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021. Electronic address: jcarcamo@enzobio.com.
Golde
David W
DW
Department of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021; Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
D002460:Cell Line; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism / Q000502:physiology*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D014162:Transfection
D020033:Protein Isoforms; D021122:Protein Subunits; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit