Title : Structural basis for activation of the receptor
tyrosine kinase
KIT by
stem cell factor
Abstract :
- Stem Cell Factor ( SCF ) initiates its multiple cellular responses by binding to the ectodomain of KIT , resulting in tyrosine kinase activation
- We describe the crystal structure of the entire ectodomain of KIT before and after SCF stimulation
- The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together
- Receptor dimerization is followed by conformational changes that enable lateral interactions between membrane proximal Ig-like domains D4 and D5 of two KIT molecules
- Experiments with cultured cells show that KIT activation is compromised by point mutations in amino acids critical for D4-D4 interaction
- Moreover, a variety of oncogenic mutations are mapped to the D5-D5 interface
- Since key hallmarks of KIT structures, ligand-induced receptor dimerization , and the critical residues in the D4-D4 interface, are conserved in other receptors , the mechanism of KIT stimulation unveiled in this report may apply for other receptor activation