Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling

Autor: Amy Stainthorp, Chi-Chuan Lin, Carlos A. Montanari, Andrei Leitão, John E. Ladbury, Lukasz Wieteska, Kin Man Suen, George S. Biggs
Rok vydání: 2019
Předmět:
Erk signalling
0301 basic medicine
Phosphotyrosine binding
MAPK/ERK pathway
Cancer Research
MAP Kinase Signaling System
Protein Conformation
Indomethacin
Antineoplastic Agents
Mechanism of action
Therapeutic repurposing
Article
Receptor tyrosine kinase
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
Cell Movement
Neoplasms
medicine
Humans
Neoplasm Invasiveness
Protein Interaction Domains and Motifs
Phosphorylation
Receptor
biology
Chemistry
Anti-Inflammatory Agents
Non-Steroidal
Drug Repositioning
Signal transducing adaptor protein
Shc PTB domain
3. Good health
Cell biology
ErbB Receptors
Molecular Docking Simulation
030104 developmental biology
Shc Signaling Adaptor Proteins
Oncology
030220 oncology & carcinogenesis
Mitogen-activated protein kinase
NEOPLASIAS
MCF-7 Cells
biology.protein
medicine.symptom
Signal transduction
HeLa Cells
Protein Binding
Zdroj: Cancer Letters
Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
ISSN: 0304-3835
Popis: Receptor tyrosine kinase (RTK)-mediated hyperactivation of the MAPK/Erk pathway is responsible for a large number of pathogenic outcomes including many cancers. Considerable effort has been directed at targeting this pathway with varying degrees of long term therapeutic success. Under non-stimulated conditions Erk is bound to the adaptor protein Shc preventing aberrant signalling by sequestering Erk from activation by Mek. Activated RTK recruits Shc, via its phosphotyrosine binding (PTB) domain (ShcPTB), precipitating the release of Erk to engage in a signalling response. Here we describe a novel approach to inhibition of MAP kinase signal transduction through attempting to preserve the Shc-Erk complex under conditions of activated receptor. A library of existing drug molecules was computationally screened for hits that would bind to the ShcPTB and block its interaction with the RTKs EGFR and ErbB2. The primary hit from the screen was indomethacin, a non-steroidal anti-inflammatory drug. Validation of this molecule in vitro and in cellular efficacy studies in cancer cells provides proof of principle of the approach to pathway down-regulation and a potential optimizable lead compound.
Highlights • Shc binds to Erk and sequesters it from MAPK signal transduction. • Inhibition of PTB domain binding to EGFR prevents release of Erk. • In silico screen identified indomethacin, a known NSAID, as an inhibitor for Shc PTB. • Indomethacin indirectly inhibits MAPK signalling by depriving the pathway of Erk. • The approach to MAPK inhibition through depleting free-Erk concentration is validated.
Databáze: OpenAIRE
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