| Termination of tyrphostin AG1478 application results in different recovery of EGF receptor tyrosine residues 1045 and 1173 phosphorylation in A431 cells. | |
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MedLine Citation:
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PMID: 19947936 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tyrphostin AG1478 is known as a specific and reversible inhibitor of TK (tyrosine kinase) activity of the EGFR [EGF (epidermal growth factor) receptor]. It is attractive as an anticancer agent for cancers with elevated EGFR TK levels. However, post-application effects of AG1478 are not well studied. We have analysed EGFR phosphorylation after termination of AG1478 application using human epidermoid carcinoma A431 cells. It was found that AG1478 inhibitory action is fast, but not fully reversible: removal of tyrphostin resulted in incomplete restoration of the overall EGFR phosphorylation. Analysing the state of two individual autophosphorylation sites of internalized EGFR, Tyr1045 and Tyr1173, we demonstrated that phosphorylation of Tyr1173 involved in stimulation of the MAPK (mitogen-activated protein kinase) cascade was restored much more efficiently than that in position 1045, which binds the ubiquitin ligase c-Cbl and is necessary for targeting the receptor for lysosomal degradation. c-Cbl association with EGFR abolished by AG1478 was not reestablished after tyrphostin cessation. As a consequence, ubiquitination-dependent EGFR delivery to lysosomes was blocked, while phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) was even increased. Thus, after termination of AG1478, the intracellular level of the inhibitor can be reached at which mitogenic signalling will be restored, whereas the EGFR negative regulation due to lysosomal degradation will not. |
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Authors:
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Kirill A Kondratov; Alexander L Chernorudskiy; Alina P Amosova; Elena S Kornilova |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-16 |
Journal Detail:
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Title: Cell biology international Volume: 34 ISSN: 1095-8355 ISO Abbreviation: Cell Biol. Int. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-12-16 Completed Date: 2010-05-04 Revised Date: 2010-11-12 |
Medline Journal Info:
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Nlm Unique ID: 9307129 Medline TA: Cell Biol Int Country: England |
Other Details:
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Languages: eng Pagination: 81-7 Citation Subset: IM |
Affiliation:
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Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Avenue 4, St Petersburg 194064, Russia. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Line, Tumor Endocytosis Humans Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Phosphorylation Proto-Oncogene Proteins c-cbl / metabolism Receptor, Epidermal Growth Factor / antagonists & inhibitors, chemistry, metabolism* Tyrosine / metabolism* Tyrphostins / pharmacology* Ubiquitination |
| Chemical | |
Reg. No./Substance:
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0/Tyrphostins; 170449-18-0/tyrphostin AG 1478; 55520-40-6/Tyrosine; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 6.3.2.-/Proto-Oncogene Proteins c-cbl |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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