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  5. MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK-mediated HER2 phosphorylation at Thr701
 
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MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK-mediated HER2 phosphorylation at Thr701

Journal
Molecular oncology
Journal Volume
11
Journal Issue
9
Date Issued
2017
Author(s)
Chen, Chia-Hung
Hsia, Te-Chun
Yeh, Ming-Hsin
Chen, Tsung-Wei
Chen, Yun-Ju
JUNG-TSU CHEN  
Wei, Ya-Ling
Tu, Chih-Yen
Huang, Wei-Chien
DOI
10.1002/1878-0261.12102
URI
https://scholars.lib.ntu.edu.tw/handle/123456789/572081
URL
https://api.elsevier.com/content/abstract/scopus_id/85025092068
Abstract
Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin-dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK-mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor-induced Akt activation.
Subjects
Akt; HER2; MEK; clathrin; resistance
SDGs

[SDGs]SDG3

Other Subjects
clathrin; epidermal growth factor receptor 2; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase kinase inhibitor; protein kinase B; small interfering RNA; epidermal growth factor; epidermal growth factor receptor; epidermal growth factor receptor 2; ERBB2 protein, human; mitogen activated protein kinase; mitogen activated protein kinase kinase; phosphothreonine; protein binding; protein kinase B; protein kinase inhibitor; Article; BT-474/HER-2+ cell line; controlled study; dimerization; downstream processing; drug resistance; enzyme activation; enzyme activity; enzyme induction; enzyme inhibition; gene overexpression; gene repression; human; human cell; MCF-7 cell line; MDA-MB-231 cell line; negative feedback; priority journal; protein phosphorylation; protein targeting; SK-BR-3 cell line; amino acid sequence; antagonists and inhibitors; biological model; chemistry; down regulation; drug effect; drug resistance; endocytosis; enzyme activation; MAPK signaling; metabolism; phosphorylation; physiological feedback; protein multimerization; tumor cell line; Amino Acid Sequence; Cell Line, Tumor; Clathrin; Down-Regulation; Drug Resistance, Neoplasm; Endocytosis; Enzyme Activation; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Phosphorylation; Phosphothreonine; Protein Binding; Protein Kinase Inhibitors; Protein Multimerization; Proto-Oncogene Proteins c-akt; Receptor, Epidermal Growth Factor; Receptor, ErbB-2
Type
journal article

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