Structural basis for stem cell factor–KIT signaling and activation of class III receptor tyrosine kinases

Stem cell factor (SCF) binds to and activates the KIT receptor, a class III receptor tyrosine kinase (RTK), to stimulate diverse processes including melanogenesis, gametogenesis and hematopoeisis. Dysregulation of KIT activation is associated with many cancers. We report a 2.5 Å crystal structure of the functional core of SCF bound to the extracellular ligand‐binding domains of KIT. The structure reveals a ‘wrapping’ SCF‐recognition mode by KIT, in which KIT adopts a bent conformation to facilitate each of its first three immunoglobulin (Ig)‐like domains to interact with SCF. Three surface epitopes on SCF, an extended loop, the B and C helices, and the N‐terminal segment, contact distinct KIT domains, with two of the epitopes undergoing large conformational changes upon receptor binding. The SCF/KIT complex reveals a unique RTK dimerization assembly, and a novel recognition mode between four‐helix bundle cytokines and Ig‐family receptors. It serves as a framework for understanding the activation mechanisms of class III RTKs.