Roles of the cytoplasmic domains of the α and β subunits of human granulocyte-macrophage colony-stimulating factor receptor

Abstract

The high-affinity and functional granulocyte-macrophage colony-stimulating factor receptor (GMR) is composed of two distinct subunits, α and β; and the cytoplasmic domain of the β subunit is essential to transduce growth-promoting signals. In contrast to the β subunit, the role of the α subunit is not well characterized. We examined the requirement of the cytoplasmic domain of the α subunit and its functional region by deletion analyses. We demonstrated that the cytoplasmic domain of the α subunit, especially 29 amino acids residues near the transmembrane domain, was absolutely required for various signaling events including activation of immediate early genes, induction of tyrosine phosphorylation of cellular proteins, and cell growth. We further analyzed the role of the cytoplasmic domain of each subunit by constructing chimeric subunits, designated α/β and β/α, by exchanging cytoplasmic domains of the α and β subunits of human (h) GMR. Reconstituted high-affinity chimeric hGMRs, hGMR(α/β,β/α) and hGMR(α/β,β), transduced signals at levels similar to the wild type hGMR(α,β) in Ba/F3 cells and in NIH3T3 cells. These observations indicate that the original configuration between the extracellular and the cytoplasmic domains of the hGMR(α,β) subunits is not required and that hGMR(α/β,β) transduced signals through the cytoplasmic domain of the β subunit in an oligomeric form, without involvement of the cytoplasmic domain of the α subunit. Therefore human granulocyte-macrophage colony-stimulating factor signals are mainly transduced through the β subunit, and the cytoplasmic domain of the α subunit is likely to activate the β subunit in the normal hGMR. (J A LLERGY C LIN I MMUNOL 1995;96:1100-14.)