The alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor interacts with c-Kit and inhibits c-Kit signaling

J Biol Chem. 2006 Aug 4;281(31):22421-22426. doi: 10.1074/jbc.M604644200. Epub 2006 Jun 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Phosphorylation
  • Protein Binding
  • Protein Isoforms
  • Protein Subunits / metabolism
  • Protein Subunits / physiology
  • Proto-Oncogene Proteins c-kit / metabolism
  • Proto-Oncogene Proteins c-kit / physiology*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / physiology*
  • Signal Transduction*
  • Stem Cell Factor / metabolism
  • Transfection

Substances

  • Protein Isoforms
  • Protein Subunits
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Stem Cell Factor
  • Proto-Oncogene Proteins c-kit