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1. The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor

Author

Dogus Murat Altintas, Simona Gallo, Cristina Basilico, Marina Cerqua, Alessio Bocedi, Annapia Vitacolonna, Orsola Botti, Elena Casanova, Ilaria Rancati, Chiara Milanese, Sara Notari, Giorgia Gambardella, Giorgio Ricci, Pier Giorgio Mastroberardino, Carla Boccaccio, Tiziana Crepaldi, and Paolo Maria Comoglio

Subjects
MET, oncogene, PSI domain, protein disulfide isomerase, protein maturation, Golgi apparatus, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

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.

Published
2022
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2. MET∆14 promotes a ligand-dependent, AKT-driven invasive growth

Author

Marina Cerqua, Orsola Botti, Maddalena Arigoni, Noemi Gioelli, Guido Serini, Raffaele Calogero, Carla Boccaccio, Paolo M Comoglio, and Dogus M Altintas

Subjects
Phosphatidylinositol 3-Kinases, Ecology, Health, Toxicology and Mutagenesis, Humans, Ligands, Oncogenes, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-met, Plant Science, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract

MET is an oncogene encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF). Upon ligand binding, MET activates multiple signal transducers, including PI3K/AKT, STAT3, and MAPK. When mutated or amplified, MET becomes a “driver” for the onset and progression of cancer. The most frequent mutations in the MET gene affect the splicing sites of exon 14, leading to the deletion of the receptor’s juxtamembrane domain (MET∆14). It is currently believed that, as in gene amplification, MET∆14 kinase is constitutively active. Our analysis of MET in carcinoma cell lines showed that MET∆14 strictly depends on HGF for kinase activation. Compared with wt MET, ∆14 is sensitive to lower HGF concentrations, with more sustained kinase response. Using three different models, we have demonstrated that MET∆14 activation leads to robust phosphorylation of AKT, leading to a distinctive transcriptomic signature. Functional studies revealed that ∆14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent ∆14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials.

Published
2022

3. Lavorare in centri per uomini violenti affrontandone l'invisibilità della violenza

Author

Caterina Arcidiacono, Fortuna Procentese, Marina Cerqua, Immacolata Di Napoli, Procentese, Fortuna, DI Napoli, Immacolata, Arcidiacono, Caterina, and Cerqua, Marina

Subjects
Health (social science), autori di violenza, violenza di genere, servizi di contrasto alla violenza di genere, benessere, Psychology, Applied Psychology
Abstract

La violenza di genere contro le donne rappresenta un problema sociale che impatta sulla salute individuale e relazionale. in Europa, ormai da più di venti anni, sono proposti programmi d'intervento per gli autori di violenza, oltre che per le vittime. La ricerca descrive come in Italia gli operatori affrontano l'intervento con uomini autori di violenza nei centri di nuova istituzione. dodici operatori sono stati intervistati sulle loro rappresentazioni e vissuti emotivi degli autori di violenza e sulle difficoltà da loro sperimentate, nonché le risorse attivate nella gestione del servizio e nella presa in carico dell'autore nella comprensione e gestione dei propri vissuti emotivi nei confronti degli autori di violenza; emerge inoltre la necessità di un lavoro di rete tra istituzioni e servizi al fine di sviluppare risposte integrate per la salute e il benessere di tutti i protagonisti della violenza di genere.

Published
2019

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