Granulocyte-macrophage colony-stimulating factor activates microtubule- associated protein 2 kinase in neutrophils via a tyrosine kinase- dependent pathway

Abstract

Receptors of the hematopoietin superfamily, including the granulocyte- macrophage colony-stimulating factor (GM-CSF) receptor, lack a tyrosine kinase domain as well as other sequences indicative of a known signaling mechanism. In this report, we identify the serine/threonine kinase, microtubule-associated protein 2 (MAP2) kinase, as an intermediate in the GM-CSF signal transduction pathway. Treatment of peripheral blood neutrophils or terminally differentiated HL-60 cells with GM-CSF induced a rapid and dose-dependent increase in MAP2 kinase activity. Maximal activity occurred within 5 minutes and the kinetics of the response varied depending on the target cell (prolonged in neutrophils and transient in neutrophilic HL-60 cells). MAP2 kinase activity in these cells correlates with the induction of a 42-Kd tyrosine phosphoprotein. Furthermore, tyrosine phosphorylation is necessary for MAP2 kinase activation since its activity is inhibited by treatment with the tyrosine kinase inhibitor, erbstatin analog. These data suggest that tyrosine phosphorylation is important in GM-CSF- mediated signal transduction and that MAP2 kinase activation may be a central biochemical event involved in its signaling.

The priming action of tumour necrosis factor-alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on neutrophils activated by inflammatory microcrystals

“…TNF-a priming is thought to proceed via increases in the tyrosine phosphorylation levels of neutrophil proteins, particularly p42MAP kinase [14,18,19,47,48], and priming effects may be blocked by the tyrosine kinase inhibitor genistein [18]. Similar increases in the tyrosine phosphorylation of neutrophil proteins (including p42MAP kinase) by GM-CSF have also been reported [14,49,50]. These findings have led to the concept of the primed neutrophil as having proteins in a transient excited state of tyrosine phosphorylation, perhaps awaiting agonist-mediated phosphorylation by serine/threonine kinases for complete activation and subsequent oxidase activation [14].…”

“…TNF-a and GM-CSF are also both reported to cause increases in PLD activation in neutrophils [45,51]. All these events may be considered short-term effects, since tyrosine phosphorylation reaches maximum levels within 5-10 min and begins to decline within 60 min [19,50]. It is possible that extended TNF-a-or GM-CSF-neutrophil incubation times may cause neutrophils to pass through their primed state to a baseline unprimed state.…”

Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on respiratory burst activity of neutrophiis in patients with myelodysplastic syndromes

“…Thus, we suggest that the diflFerence in maximal priming effect between rhG-CSF and rhGM-CSF is ascribed to the difference of these intracellular metabolic events. It has been recently reported that the tyrosine-phosphorylated 42-kD protein in human neutrophils is the microtubule-associated protein 2 kinase [31,32].…”

Growth Factor Induction of Cytosolic Protein Tyrosine Kinase Activity in Human Haemopoietic Progenitor Cells Isolated by Flow Cytometry

“…For example, certain haemopoietic growth factors ligate receptor tyrosine kinases, such as c-kit and flk-2 (Williams et al, 1990;Broxmeyer et al, 1991;Ratajczak et al, 1992;Rottapel et al, 1991;Lyman et al, 1993). Second, immunoblot analysis demonstrates the appearance of several tyrosine phosphorylated proteins when certain cell lines are exposed to haemopoietic growth factors Okuda et al, 1992;Raines et al, 1992;Alai et al, 1992;Hallek et al, 1992). Third, inhibitors of cellular tyrosine kinases prevent growth factor induction of proliferation of haemopoietic progenitors (Carlo-Stella et al, 1996).…”