Distinct domains of the human granulocyte-macrophage colony-stimulating factor receptor α subunit mediate activation of Jak/Stat signaling and differentiation

Michael B. Lilly, Marina Zemskova, Arthur E. Frankel, Jonathan Salo, Andrew S. Kraft

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

The α subunit of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor has several isoforms that result from alternative splicing events. Two forms, α-1 and α-2, have intracytoplasmic sequences that are identical within a membrane-proximal domain but differ completely distally. Variant and mutated GM-CSF receptor α subunits, along with the β subunit (βc protein)were expressed in M1 murine leukemia cells, and the ability of the receptors to signal for differentiation events and to activate Jak/Stat signaling pathways was examined. All cell lines expressing both α and βc proteins exhibited high-affinity binding of radiolabeled human GM-CSF. Receptor α subunits with intact membrane-proximal intracellular domains could induce expression of the macrophage antigen F4/80 and down-regulate the expression of CD11b. Addition of recombinant human GM-CSF to cells expressing α-1 subunits induced the expression of CD86 and tyrosine phosphorylation of Jak-2 and its putative substrates SHPTP-2, Stat-5, and the GM-CSF receptor βc subunit. Cells containing α subunits that lacked a distal domain (term-3) or had the alternatively spliced α-2 distal domain showed markedly decreased ability to support tyrosine phosphorylation of Jak-2 and its substrates or to up-regulate CD86. Ligand binding induced stable association of the α-1 subunit and βc protein. In contrast, the α-2 subunit did not stably associate with the βc subunit. These data identify potential molecular mechanisms for differential signaling of the α-1 and α-2 proteins. The association of unique signaling events with the 2 active GM-CSF α subunit isoforms offers a model for variable response phenotypes to the same ligand.

Original languageEnglish (US)
Pages (from-to)1662-1670
Number of pages9
JournalBlood
Volume97
Issue number6
DOIs
StatePublished - Mar 15 2001

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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