GM-CSF–activated signaling modules. PI3K93,–95 : GM-CSF induces activation of the class IA PI3Ks, which consist of 2 subunits: a catalytic subunit, p110, and a regulatory subunit, p85. Activity of PI3K is promoted by JAK2-mediated phosphorylation of p85. On activation, PI3K functions mainly through the generation of PtdIns(3,4,5)P3 (PIP3), an activity counteracted by phosphatases PTEN and SHIP. PIP3 acts as a second messenger, regulating a large variety of downstream targets, including protein kinase B (PKB; also called c-AKT). By recruiting PKB to the plasma membrane, PIP3 enables its activation through phosphorylation by PDK1 and mTORC2. Activated PKB regulates many targets, including the FOXO transcription factors, the TSC1/TSC2 complex, and the mTOR complex 1 (mTORC1). Like FOXO, mTORC1 acts through the regulation of transcription, but its main function is in the regulation of protein translation. JAK/STAT90 : STAT proteins as well as Src kinases are recruited to βc by their SH2 domains that interact with phosphorylated Y612, Y695, and Y750. The STATs are primarily phosphorylated by JAK2, but kinase activity of the Src kinases has also been reported. STAT phosphorylation at a conserved tyrosine residue alters their conformation, which allows the formation of homodimers or heterodimers with DNA-binding and transcription-regulating ability. These dimers then translocate to the nucleus where they act as functional transcription factors. MAPK59 : Although the human MAPK family includes at least 11 members subdivided into 6 groups, the principle MAPK pathway activated by the GM-CSF receptor is the MEK/ERK pathway. Recruitment of mSOS to the SHC/GRB2 complex enables mSOS to catalyze RAS activation. Formation of active GTP-bound RAS from inactive GDP-bound RAS leads to the successive activation of RAF, MEK, and ERK. On activation, ERK expresses kinase activity toward a variety of cytoplasmic molecules and nuclear proteins, which in turn regulate gene expression. NF-κB127 : In resting cells, canonical NF-κB dimers consisting of NF-κB/Rel family members RelA, c-Rel, p50, and/or p52 are retained in the cytoplasm by binding to inhibitor of NF-κB proteins (IκBs). Activation is achieved through the IKK complex, which phosphorylates IκB proteins. These are subsequently ubiquitinated and finally degraded, enabling nuclear translocation of canonical NF-κB dimers.
