title: Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.
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.
authors: Center for Cell Decision Processes, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Laura B
authors: LB
authors: Kleiman
authors: Thomas
authors: T
authors: Maiwald
authors: Holger
authors: H
authors: Conzelmann
authors: Douglas A
authors: DA
authors: Lauffenburger
authors: Peter K
authors: PK
authors: Sorger
mesh_terms: D001665:Binding Sites; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D000077341:Lapatinib; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010766:Phosphorylation; D011799:Quinazolines / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D066246:ErbB Receptors; D000077156:Gefitinib; D000077341:Lapatinib; D004364:Pharmaceutical Preparations; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3