Activation of mitogen-activated protein kinase pathways by the granulocyte colony-stimulating factor receptor: mechanisms and functional consequences.

The cytokine Granulocyte Colony Stimulating Factor (G-CSF) promotes proliferation, differentiation, survival and functional maturation of cells within the neutrophilic granulocyte lineage. G-CSF binds to its cell-surface receptor (G-CSFR) causing activation via homodimerisation and subsequent phosphorylation on four tyrosine residues of the receptor intracellular domain. This initiates a range of intracellular signalling events including the activation of Mitogen-Activated Protein Kinase (MAPK) pathways. G-CSF stimulates activation of the ERK 1/2 pathway, as well as the stress-activated JNK and p38 pathways, and the less-characterised ERK5/Big MAPK 1 pathway. Receptor mutagenesis studies have aided in the identification of regions of the G-CSFR that mediate specific activation of these MAPK pathways. In addition, the activation of individual MAPK pathways appears to contribute to distinct biological outcomes. Thus, MAPK activation may be an important mediator of the actions of G-CSF.