TY - JOUR
T1 - The STRENGTH AND COOPERATIVITY of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer
AU - Reshetnyak, Andrey V.
AU - Opatowsky, Yarden
AU - Boggon, Titus J.
AU - Folta-Stogniew, Ewa
AU - Tome, Francisco
AU - Lax, Irit
AU - Schlessinger, Joseph
N1 - Publisher Copyright: © 2015 Elsevier Inc.
PY - 2015/1/8
Y1 - 2015/1/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84920559004&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.molcel.2014.11.021
DO - https://doi.org/10.1016/j.molcel.2014.11.021
M3 - مقالة
C2 - 25544564
SN - 1097-2765
VL - 57
SP - 191
EP - 201
JO - Molecular Cell
JF - Molecular Cell
IS - 1
ER -