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Mol Cell. 2015 Jan 8;57(1):191-201. doi: 10.1016/j.molcel.2014.11.021. Epub 2014 Dec 24.

The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
The Biophysical Resource, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: irit.lax@yale.edu.
4
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: joseph.schlessinger@yale.edu.

Abstract

The receptor tyrosine kinase KIT plays an important role in development of germ cells, hematopoietic cells, and interstitial pacemaker cells. Oncogenic KIT mutations play an important "driver" role in gastrointestinal stromal tumors, acute myeloid leukemias, and melanoma, among other cancers. Here we describe the crystal structure of a recurring somatic oncogenic mutation located in the C-terminal Ig-like domain (D5) of the ectodomain, rendering KIT tyrosine kinase activity constitutively activated. The structural analysis, together with biochemical and biophysical experiments and detailed analyses of the activities of a variety of oncogenic KIT mutations, reveals that the strength of homotypic contacts and the cooperativity in the action of D4D5 regions determines whether KIT is normally regulated or constitutively activated in cancers. We propose that cooperative interactions mediated by multiple weak homotypic contacts between receptor molecules are responsible for regulating normal ligand-dependent or oncogenic RTK activation via a "zipper-like" mechanism for receptor activation.

PMID:
25544564
PMCID:
PMC4764128
DOI:
10.1016/j.molcel.2014.11.021
[Indexed for MEDLINE]
Free PMC Article

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