PROTEIN-TYROSINE KINASES IN GRANULOCYTE-COLONY-STIMULATING FACTOR-RECEPTOR SIGNAL-TRANSDUCTION, MYELOID CELL-PROLIFERATION, AND NEUTROPHIL ACTIVATION

Granulocyte colony-stimulating factor (G-CSF) plays an important role in the growth and maturation of granulocytic precursor cells. Although the interaction between G-CSF and its receptor (G-CSF-R) is an obliga tory event during proliferation and differentiation of myeloid cells, the signal transduction mechanisms leading to these effects are not co mpletely known. We investigated the kinetics of protein tyrosine kinas e (PTK) activation in G-CSF-R signal transduction in myeloid leukemic cell lines and peripheral blood neutrophils. G-CSF treatment of myeloi d cell-lines (HL-60, KG-1, NFS-60) and neutrophils resulted in a rapid increase in PTK activity. This induction was inhibited by an anti-G-C SF monoclonal antibody and various PTK-specific inhibitors. PTK activi ty was important for proliferation of myeloid cells; its inhibition re sulted in decreased proliferation and clonogenicity of these cells. PT K-induction was not involved in G-CSF-R expression, internalization or recycling, but was partially responsible for up-regulation of CD11b e xpression on neutrophils. In contrast to neutrophilic cell-lines, the myelo-monocytic cell lines (U-937, WEHI-3B) showed no change in PTK le vels in response to G-CSF. The results indicate that the G-CSF-R-media ted PTK up-regulation may be a neutrophil-lineage-restricted signal, a nd that PTK may play an important role in the proliferation of neutrop hil-precursors and functional activation of mature neutrophils.