Schematic representation of the activated CSF3R complex. Boxes 1 and 2 denote conserved regions for binding of JAK kinases. After CSF3-induced homodimerization of CSF3R chains, JAKs phosphorylate 4 receptor tyrosine residues, and STAT proteins. PI-3K/Akt, STAT5, and p21Ras-ERK1/2 signaling promote cell survival and proliferation, whereas STAT3, SOCS3, and SHIP promote cell cycle arrest and neutrophil differentiation in myeloid cell line models. The region affected by nonsense mutations in SCN is indicated. The resulting truncations lead to the loss of a di-leucine motif critical for receptor internalization, and of a docking site for SOCS3 (Y729) important for lysosomal routing of CSF3R.⁴³