GM-CSF Signaling

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells like monocytes, eosinophils, basophils, neutrophils and dendritic cells. GM-CSF is mainly produced by activated T-cells when Runx1 (also known as acute myeloid leukemia 1 -AML1), a transcription factor essential for hematopoiesis binds calcineurin A/B and mediates the transcriptional activation of GM-CSF.GM-CSF receptor is a transmembrane receptor with a ligand binding α subunit and a βc subunit that it shares with IL-3 and IL-5. Ligand binding induces tyrosine phosphorylation of βc as well as a number of cytoplasmic proteins including various kinases and adaptor proteins. When GM-CSF binds its receptor, adaptor molecules GRB2 (growth factor receptor bound protein 2), SOS (son of sevenless) and Shc form a signaling complex that activates the Ras/Raf/MEK/ERK pathway. GM-CSF also activates the myeloid-restricted Src kinase, Hck, followed downstream by the PI3K/Akt pathway. In a third pathway, tyrosine phosphorylation of JAK2 leads to the downstream activation of STAT1/STAT3/STAT5. Downstream molecules in the various pathways are translocated into the nucleus where they are involved in the induction of genes like Bcl-XL, cyclin D1 and PIM1 that promote cell survival, proliferation and differentiation.