TY - JOUR
T1 - A putative mechanism for downregulation of the catalytic activity of the EGF receptor via direct contact between its kinase and C-terminal domains
AU - Landau, Meytal
AU - Fleishman, Sarel J.
AU - Ben-Tal, Nir
N1 - Funding Information:
We thank Tony Hunter, Antony Burgess, Joseph Schlessinger, Idit Kopatz, Amit Kessel, and Saul Yankofsky for their critical comments on the manuscript, Miriam Eisenstein for her help in the identification of the dimeric conformation of the EGFR kinase, and Lisa Shewchuk for sharing the coordinates of the EGFR/GW572016 structure before their release. This study was supported by a grant from the Israel Cancer Association (ICA) and by a Research Career Development Award from the Israel Cancer Research Fund (ICRF) to N.B.-T. S.J.F. was supported by a doctoral fellowship from the Clore Israel Foundation. M.L. was supported by a Travel Scholarship from the Constantiner Institute for Molecular Genetics.
PY - 2004/12
Y1 - 2004/12
N2 - Tyrosine kinase receptors of the EGFR family play a significant role in vital cellular processes and in various cancers. EGFR members are unique among kinases, as the regulatory elements of their kinase domains are constitutively ready for catalysis. Nevertheless, the receptors are not constantly active. This apparent paradox has prompted us to seek mechanisms of regulation in EGFR's cytoplasmic domain that do not involve conformational changes of the kinase domain. Our computational analyses, based on the three-dimensional structure of EGFR's kinase domain suggest that direct contact between the kinase and a segment from the C-terminal regulatory domains inhibits enzymatic activity. EGFR activation would then involve temporal dissociation of this stable complex, for example, via ligand-induced contact formation between the extracellular domains, leading to the reorientation of the transmembrane and intracellular domains. The model provides an explanation at the molecular level for the effects of several cancer-causing EGFR mutations.
AB - Tyrosine kinase receptors of the EGFR family play a significant role in vital cellular processes and in various cancers. EGFR members are unique among kinases, as the regulatory elements of their kinase domains are constitutively ready for catalysis. Nevertheless, the receptors are not constantly active. This apparent paradox has prompted us to seek mechanisms of regulation in EGFR's cytoplasmic domain that do not involve conformational changes of the kinase domain. Our computational analyses, based on the three-dimensional structure of EGFR's kinase domain suggest that direct contact between the kinase and a segment from the C-terminal regulatory domains inhibits enzymatic activity. EGFR activation would then involve temporal dissociation of this stable complex, for example, via ligand-induced contact formation between the extracellular domains, leading to the reorientation of the transmembrane and intracellular domains. The model provides an explanation at the molecular level for the effects of several cancer-causing EGFR mutations.
UR - http://www.scopus.com/inward/record.url?scp=9944246020&partnerID=8YFLogxK
U2 - 10.1016/j.str.2004.10.006
DO - 10.1016/j.str.2004.10.006
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C2 - 15576039
AN - SCOPUS:9944246020
SN - 0969-2126
VL - 12
SP - 2265
EP - 2275
JO - Structure
JF - Structure
IS - 12
ER -