Figure 2.

CSF1 signaling leading to ETS2 activation. A simplified view of CSF1 signal transduction. For a more detailed review see Stanley & Chitu.⁶⁰ CSF1 binding leads to receptor (CSF1R) leads to dimerization and autophosphorylation which initiates a phosphorylation cascade through RAS (HRAS, KRAS, NRAS genes), RAF (RAF1, BRAF, ARAF), MEK (MAP2K1, MAP2K2) and ERK1,2 (MAPK3/MAPK1) to phosphorylate ETS2 (P = phosphate group). ETS2 moves to the nucleus where it interacts with PU.1 (SPI1) or AP1 complexes to activate transcription of target genes including CSF1R and PLAU. The signaling cascade is subject to feedback at every level. The CSF1R-CSF1 complex is dephosphorylated, internalised and degraded.⁶⁰ The diagram shows two examples highlighted in the text. MEK phosphorylates ERK on threonine and tyrosine. Activated ERK acts in a feedback loop to inhibit RAF phosphorylation. The inducible dual specificity phosphatase DUSP1 dephosphorylates and inactivates ERK.