KIT signaling in gastrointestinal stromal tumors (GIST)

Physiologic KIT activation is triggered by binding of the dimeric KIT ligand (SCF) to the extracellular, ligand-binding domain of the KIT receptor tyrosine kinase. This in turn leads to homodimerization of two KIT molecules, which is accompanied by structural changes in the receptor and activation (autophosphorylation) of the intracellular KIT kinase domain. The phosphorylated tyrosine residues on KIT serve as binding sites for various cell signaling proteins, resulting in the activation of various signaling cascades, such as the PI3K/AKT/mTOR, RAS/RAF/MAPK, and the JAK/STAT pathways. Ultimately, the activated KIT receptor stimulates intracellular signaling pathways controlling cell proliferation, adhesion, apoptosis, survival, and differentiation.