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The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor
The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein...
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/PMC9604360/ https://www.ncbi.nlm.nih.gov/pubmed/36293286 http://dx.doi.org/10.3390/ijms232012427 |
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author | Altintas, Dogus Murat Gallo, Simona Basilico, Cristina Cerqua, Marina Bocedi, Alessio Vitacolonna, Annapia Botti, Orsola Casanova, Elena Rancati, Ilaria Milanese, Chiara Notari, Sara Gambardella, Giorgia Ricci, Giorgio Mastroberardino, Pier Giorgio Boccaccio, Carla Crepaldi, Tiziana Comoglio, Paolo Maria |
author_facet | Altintas, Dogus Murat Gallo, Simona Basilico, Cristina Cerqua, Marina Bocedi, Alessio Vitacolonna, Annapia Botti, Orsola Casanova, Elena Rancati, Ilaria Milanese, Chiara Notari, Sara Gambardella, Giorgia Ricci, Giorgio Mastroberardino, Pier Giorgio Boccaccio, Carla Crepaldi, Tiziana Comoglio, Paolo Maria |
author_sort | Altintas, Dogus Murat |
collection | PubMed |
description | The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases (PDI). Using a scrambled oxidized RNAse enzymatic activity assay in vitro, we show, for the first time, that the MET extracellular domain displays disulfide isomerase activity, abolished by PSI domain antibodies. PSI domain deletion or mutations of CXXC sites to AXXA or SXXS result in a significant impairment of the cleavage of the MET 175 kDa precursor protein, abolishing the maturation of α and β chains, of, respectively, 50 kDa and 145 kDa, disulfide-linked. The uncleaved precursor is stuck in the Golgi apparatus and, interestingly, is constitutively phosphorylated. However, no signal transduction is observed as measured by AKT and MAPK phosphorylation. Consequently, biological responses to the MET ligand—hepatocyte growth factor (HGF)—such as growth and epithelial to mesenchymal transition, are hampered. These data show that the MET PSI domain is functional and is required for the maturation, surface expression, and biological functions of the MET oncogenic protein. |
format | Online Article Text |
id | pubmed-9604360 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96043602022-10-27 The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor Altintas, Dogus Murat Gallo, Simona Basilico, Cristina Cerqua, Marina Bocedi, Alessio Vitacolonna, Annapia Botti, Orsola Casanova, Elena Rancati, Ilaria Milanese, Chiara Notari, Sara Gambardella, Giorgia Ricci, Giorgio Mastroberardino, Pier Giorgio Boccaccio, Carla Crepaldi, Tiziana Comoglio, Paolo Maria Int J Mol Sci Article The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases (PDI). Using a scrambled oxidized RNAse enzymatic activity assay in vitro, we show, for the first time, that the MET extracellular domain displays disulfide isomerase activity, abolished by PSI domain antibodies. PSI domain deletion or mutations of CXXC sites to AXXA or SXXS result in a significant impairment of the cleavage of the MET 175 kDa precursor protein, abolishing the maturation of α and β chains, of, respectively, 50 kDa and 145 kDa, disulfide-linked. The uncleaved precursor is stuck in the Golgi apparatus and, interestingly, is constitutively phosphorylated. However, no signal transduction is observed as measured by AKT and MAPK phosphorylation. Consequently, biological responses to the MET ligand—hepatocyte growth factor (HGF)—such as growth and epithelial to mesenchymal transition, are hampered. These data show that the MET PSI domain is functional and is required for the maturation, surface expression, and biological functions of the MET oncogenic protein. MDPI 2022-10-17 /pmc/articles/PMC9604360/ /pubmed/36293286 http://dx.doi.org/10.3390/ijms232012427 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 Altintas, Dogus Murat Gallo, Simona Basilico, Cristina Cerqua, Marina Bocedi, Alessio Vitacolonna, Annapia Botti, Orsola Casanova, Elena Rancati, Ilaria Milanese, Chiara Notari, Sara Gambardella, Giorgia Ricci, Giorgio Mastroberardino, Pier Giorgio Boccaccio, Carla Crepaldi, Tiziana Comoglio, Paolo Maria The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor |
title | The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor |
title_full | The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor |
title_fullStr | The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor |
title_full_unstemmed | The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor |
title_short | The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor |
title_sort | psi domain of the met oncogene encodes a functional disulfide isomerase essential for the maturation of the receptor precursor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9604360/ https://www.ncbi.nlm.nih.gov/pubmed/36293286 http://dx.doi.org/10.3390/ijms232012427 |
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