Human granulocyte-macrophage colony-stimulating factor receptor signal transduction requires the proximal cytoplasmic domains of the α and β subunits

M. Weiss, C. Yokoyama, Y. Shikama, C. Naugle, B. Druker, C. A. Sieff

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) controls the production, maturation, and function of cells in multiple hematopoietic lineages. These effects are mediated by a cell-surface receptor (GM-R) composed of α and β subunits, each containing 378 and 881 amino acids, respectively. Whereas the α subunit exists as several isoforms that bind GM- CSF with low affinity, the β common subunit (βc) does not bind GM-CSF itself, but acts as a high-affinity converter for GM-CSF, interleukin-3 (IL- 3), and IL-5 receptor α subunits. The cytoplasmic region of GM-Rα consists of a membrane-proximal conserved region shared by the α1 and α2 isoforms and a C-terminal variable region that is divergent between α1 and α2. The cytoplasmic region of βc contains membrane proximal serine and acidic domains. To investigate the amino acid sequences that influence signal transduction by this receptor complex, we constructed a series of cytoplasmic truncation mutants of the α2 and β subunits. To study these truncations, we stably transfected the IL-3-dependent murine cell line Ba/F3 with wild-type or mutant cDNAs. We found that the wild-type and mutant α subunits conferred similar low-affinity binding sites for human GM-CSF to Ba/F3, and the wild- type or mutant β subunit converted some of these sites to high-affinity; the cytoplasmic domain of β was unnecessary for this high-affinity conversion. Proliferation assays showed that the membrane-proximal conserved region of GM-Rα and the serine-acidic domain of βc are required for both cell proliferation and ligand-dependent phosphorylation of a 93-kD cytoplasmic protein. We suggest that these regions may represent an important signal transduction motif present in several cytokine receptors.

Original languageEnglish (US)
Pages (from-to)3298-3306
Number of pages9
JournalBlood
Volume82
Issue number11
DOIs
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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