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MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor
SIMPLE SUMMARY: The MET oncogene, encoding the tyrosine kinase receptor for a hepatocyte growth factor (HGF), plays a key role in the onset and progression of aggressive forms of breast cancer. Recently, it was found that the glutamate receptor, which has a well-known role in the nervous system, is...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496780/ https://www.ncbi.nlm.nih.gov/pubmed/36139568 http://dx.doi.org/10.3390/cancers14184408 |
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author | Gallo, Simona Vitacolonna, Annapia Comoglio, Paolo Crepaldi, Tiziana |
author_facet | Gallo, Simona Vitacolonna, Annapia Comoglio, Paolo Crepaldi, Tiziana |
author_sort | Gallo, Simona |
collection | PubMed |
description | SIMPLE SUMMARY: The MET oncogene, encoding the tyrosine kinase receptor for a hepatocyte growth factor (HGF), plays a key role in the onset and progression of aggressive forms of breast cancer. Recently, it was found that the glutamate receptor, which has a well-known role in the nervous system, is expressed in many types of tumors outside the nervous system and contributes to metastatic behavior in breast cancer cells. Here, we highlight that MET protein physically interacts with glutamate receptors in two highly metastatic breast cancer cell lines. HGF, which creates a supportive proinvasive microenvironment for the tumor cells, stabilizes this interaction. Pharmacological inhibition of glutamate receptors blunts the migration and invasion elicited by HGF, suggesting drug repurposing of glutamate receptor antagonists for anticancer therapy. ABSTRACT: The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel involved in excitatory synaptic transmission. Outside the nervous system, the NMDAR is expressed in a variety of tissues and in cancers, notably in the highly invasive and metastatic triple-negative breast carcinoma. MET encodes the tyrosine kinase receptor for HGF and is a master regulator gene for “invasive growth”. In silico analysis shows that high expression of the NMDAR2B subunit is a negative prognostic factor in human invasive breast carcinoma. Here, we show that in triple-negative breast cancer cell lines NMDAR2B and MET proteins are coexpressed. HGF stimulation of these cells is followed by autophosphorylation of the MET kinase and phosphorylation of the NMDAR2B subunit at tyrosines 1252 and 1474. MET and phosphorylated NMDAR2B are physically associated, as demonstrated by co-immunoprecipitation, confocal immunofluorescence, and proximity ligation assays. Notably, pharmacological inhibition of NMDAR by MK801 and ifenprodil blunts the biological response to HGF. These results demonstrate the existence of a MET-NMDAR crosstalk driving the invasive program, paving the way for a new combinatorial therapy. |
format | Online Article Text |
id | pubmed-9496780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94967802022-09-23 MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor Gallo, Simona Vitacolonna, Annapia Comoglio, Paolo Crepaldi, Tiziana Cancers (Basel) Article SIMPLE SUMMARY: The MET oncogene, encoding the tyrosine kinase receptor for a hepatocyte growth factor (HGF), plays a key role in the onset and progression of aggressive forms of breast cancer. Recently, it was found that the glutamate receptor, which has a well-known role in the nervous system, is expressed in many types of tumors outside the nervous system and contributes to metastatic behavior in breast cancer cells. Here, we highlight that MET protein physically interacts with glutamate receptors in two highly metastatic breast cancer cell lines. HGF, which creates a supportive proinvasive microenvironment for the tumor cells, stabilizes this interaction. Pharmacological inhibition of glutamate receptors blunts the migration and invasion elicited by HGF, suggesting drug repurposing of glutamate receptor antagonists for anticancer therapy. ABSTRACT: The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel involved in excitatory synaptic transmission. Outside the nervous system, the NMDAR is expressed in a variety of tissues and in cancers, notably in the highly invasive and metastatic triple-negative breast carcinoma. MET encodes the tyrosine kinase receptor for HGF and is a master regulator gene for “invasive growth”. In silico analysis shows that high expression of the NMDAR2B subunit is a negative prognostic factor in human invasive breast carcinoma. Here, we show that in triple-negative breast cancer cell lines NMDAR2B and MET proteins are coexpressed. HGF stimulation of these cells is followed by autophosphorylation of the MET kinase and phosphorylation of the NMDAR2B subunit at tyrosines 1252 and 1474. MET and phosphorylated NMDAR2B are physically associated, as demonstrated by co-immunoprecipitation, confocal immunofluorescence, and proximity ligation assays. Notably, pharmacological inhibition of NMDAR by MK801 and ifenprodil blunts the biological response to HGF. These results demonstrate the existence of a MET-NMDAR crosstalk driving the invasive program, paving the way for a new combinatorial therapy. MDPI 2022-09-11 /pmc/articles/PMC9496780/ /pubmed/36139568 http://dx.doi.org/10.3390/cancers14184408 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gallo, Simona Vitacolonna, Annapia Comoglio, Paolo Crepaldi, Tiziana MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor |
title | MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor |
title_full | MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor |
title_fullStr | MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor |
title_full_unstemmed | MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor |
title_short | MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor |
title_sort | met oncogene controls invasive growth by coupling with nmda receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496780/ https://www.ncbi.nlm.nih.gov/pubmed/36139568 http://dx.doi.org/10.3390/cancers14184408 |
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