RAPID ACTIVATION OF THE STAT3 TRANSCRIPTION FACTOR BY GRANULOCYTE-COLONY-STIMULATING FACTOR

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that s timulates proliferation and differentiation of progenitor cells of neu trophils by signaling through its receptor (G-CSFR). Although the G-CS FR belongs to the cytokine receptor superfamily, which lacks an intrac ellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellu lar proteins is critical for its biologic activities. We report here t hat JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in resp onse to G-CSF induction. We also demonstrate that the DNA-binding prot ein STAT3 (also called the acute-phase response factor [APRF], activat ed by interleukin-6) is an early target of G-CSF-induced tyrosine phos phorylation. G-CSF induces two DNA-binding complexes; the major comple x contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins . Antiphosphotyrosine antibody interferes with the DNA binding activit y of activated STAT3, indicating that tyrosine phosphorylation of STAT 3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF. (C) 1994 by The American Society of Hematology.