Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.

TitleRapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.
Publication TypeJournal Article
Year of Publication2011
AuthorsKleiman, LB, Maiwald, T, Conzelmann, H, Lauffenburger, DA, Sorger, PK
JournalMol Cell
Volume43
Issue5
Pagination723-37
Date Published2011 Sep 2
ISSN1097-4164
KeywordsBinding Sites, Humans, Models, Biological, Pharmaceutical Preparations, Phosphorylation, Quinazolines, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Receptor, erbB-2, Receptor, erbB-3, Signal Transduction, Tumor Cells, Cultured
Abstract

Epidermal growth factor receptors (ErbB1-4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100-1000 times in the course of a typical immediate-early response to ligand. Rapid phospho-turnover is also observed for EGF-activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases. Thus, the complexes formed on the cytoplasmic tail of active receptors and the downstream signaling kinases they control are highly dynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mechanisms of action.

DOI10.1016/j.molcel.2011.07.014
Alternate JournalMol. Cell
PubMed ID21884975
PubMed Central IDPMC3222462
Grant ListCA112967 / CA / NCI NIH HHS / United States
GM68762 / GM / NIGMS NIH HHS / United States
P50 GM068762-08 / GM / NIGMS NIH HHS / United States
U54 CA112967-07 / CA / NCI NIH HHS / United States