Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor

Satoru Yuzawa, Yarden Opatowsky, Zhongtao Zhang, Valsan Mandiyan, Irit Lax, Joseph Schlessinger

Research output: Contribution to journalArticlepeer-review

270 Scopus citations


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.

Original languageEnglish
Pages (from-to)323-334
Number of pages12
Issue number2
StatePublished - 27 Jul 2007
Externally publishedYes

Bibliographical note

Funding Information:
S.Y. was supported by a fellowship from the Uehara Memorial Foundation, and Y.O. is supported by a Cancer Research Institute postdoctoral fellowship. We thank Titus Boggon for valuable advice about the manuscript. This work was supported by NIH grants AR 051448, AR 051886, and P50 AR 054086. We thank Yoav Peleg from the Weizmann Institute for the GST-Endoglycosidase F1 plasmid and Brigitte D'arcy from Roche, Basel who provided the original plasmid. We also thank the staff of NSLS at beamlines X6A, X12B, X12C, X25, X26C, and X29.




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