GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR STIMULATES JAK2 SIGNALING PATHWAY AND RAPIDLY ACTIVATES P93(FES), STAT1 P91, AND STAT3 P92IN POLYMORPHONUCLEAR LEUKOCYTES

Granulocyte-macrophage colony-stimulating factor (GM-CSF), supports pr oliferation, differentiation, and functional activation of hemopoietic cells by its interaction with a heterodimeric receptor. Although GM-C SF receptor is devoid of tyrosine kinase enzymatic activity, GM-CSF-in duced peripheral blood polymorphonuclear leukocytes (PMN) functional a ctivation is mediated by the phosphorylation of a large number of intr acellular signaling molecules. We have previously shown that JAK2 beco mes tyrosine-phosphorylated in response to GM-CSF in PMN. In the prese nt study we demonstrate that also the signal transducers and activator s of transcription (STAT) family members STAT1 p91 and STAT3 p92 and t he product of the c-fps/fes protooncogene become tyrosine-phosphorylat ed upon GM-CSF stimulation and physically associated with both GM-CSF receptor beta common subunit and JAK2. Moreover GM-CSF was able to ind uce JAK2 and p93(fes) catalytic activity. We also demonstrate that the association of the GM-CSF receptor beta common subunit with JAK2 is l igand-dependent. Finally we demonstrate that GM-CSF induces a DNA-bind ing complex that contains both p91 and p92, These results identify a n ew signal transduction pathway activated by GM-CSF and provide a mecha nism for rapid activation of gene expression in GM-CSF-stimulated PMN.