Titre :

Trop-2, na ⁺/k ⁺ atpase, cd9, pkc?, cofilin assemble a membrane signaling super-complex that drives colorectal cancer growth and invasion

Auteur(s) :

Guerra, Emanuela [Auteur]
Relli, Valeria [Auteur]
Ceci, Martina [Auteur]
Tripaldi, Romina [Auteur]
Simeone, Pasquale [Auteur]
Università degli studi "G. d'Annunzio" Chieti-Pescara [Chieti-Pescara] [Ud'A]
Aloisi, Anna Laura [Auteur]
Pantalone, Ludovica [Auteur]
La Sorda, Rossana [Auteur]
Lattanzio, Rossano [Auteur]
Università degli studi "G. d'Annunzio" Chieti-Pescara [Chieti-Pescara] [Ud'A]
Sacchetti, Andrea [Auteur]
Havas, Kristina [Auteur]
Guarnieri, Simone [Auteur]
Vergara, Daniele [Auteur]
Università del Salento = University of Salento [Lecce]
Fournier, Isabelle [Auteur]
Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
Salzet, Michel [Auteur]
Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
Tinari, Nicola [Auteur]
Università degli studi "G. d'Annunzio" Chieti-Pescara [Chieti-Pescara] [Ud'A]
Piantelli, Mauro [Auteur]
Trerotola, Marco [Auteur]
Università degli studi "G. d'Annunzio" Chieti-Pescara [Chieti-Pescara] [Ud'A]
Alberti, Saverio [Auteur]
Università degli studi "G. d'Annunzio" Chieti-Pescara [Chieti-Pescara] [Ud'A]

Titre de la revue :

Oncogene

Nom court de la revue :

Oncogene

Éditeur :

Nature Publishing Group [1987-....]

Date de publication :

2022-02-07

ISSN :

1476-5594

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

Trop-2 is a transmembrane signal transducer that is overexpressed in most human cancers, and drives malignant progression. To gain knowledge on the higher-order molecular mechanisms that drive Trop-2 signaling, we applied ...
Lire la suite >Trop-2 is a transmembrane signal transducer that is overexpressed in most human cancers, and drives malignant progression. To gain knowledge on the higher-order molecular mechanisms that drive Trop-2 signaling, we applied next-generation sequencing, proteomics, and high-resolution microscopy to models and primary cases of human colorectal cancer (CRC). We had previously shown that Trop-2 induces a Ca(2+) signal. We reveal here that Trop-2 binds the cell membrane Na(+)/K(+)-ATPase, and that clustering of Trop-2 induces an intracellular Ca(2+) rise followed by membrane translocation of PKCalpha, which in turn phosphorylates the Trop-2 cytoplasmic tail. This feed-forward signaling is promoted by the binding of Trop-2 to the PKCalpha membrane-anchor CD9. CRISPR-based inactivation of CD9 in CRC cells shows that CD9 is required by Trop-2 for recruiting PKCalpha and cofilin-1 to the cell membrane. This induces malignant progression through proteolytic cleavage of E-cadherin, remodeling of the beta-actin cytoskeleton, and activation of Akt and ERK. The interaction between Trop-2 and CD9 was validated in vivo in murine models of CRC growth and invasion. Overexpression of the components of this Trop-2-driven super-complex significantly worsened disease-free and overall survival of CRC patients, supporting a pivotal relevance in CRC malignant progression. Our findings demonstrate a previously unsuspected layer of cancer growth regulation, which is dormant in normal tissues, and is activated by Trop-2 in cancer cells.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

INSERM
Université de Lille

Collections :

• Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192

Date de dépôt :

2022-06-15T13:58:24Z
2025-04-01T08:21:09Z