The receptor protein tyrosine phosphatase PTPRJ negatively modulates the CD98hc oncoprotein in lung cancer cells
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Sabrina D’Agostino1, Delia Lanzillotta1, Mariaconcetta Varano1, Cirino Botta1, Antonio Baldrini1, Anna Bilotta1, Stefania Scalise1, Vincenzo Dattilo2, Rosario Amato2, Eugenio Gaudio1,3, Francesco Paduano1,4, Camillo Palmieri1, Rodolfo Iuliano1, Nicola Perrotti2, Cesare Indiveri5, Alfredo Fusco6, Marco Gaspari1 and Francesco Trapasso1
1Dipartimento di Medicina Sperimentale e Clinica, University Magna Græcia, Campus “S. Venuta”, Catanzaro, Italy
2Dipartimento di Scienze della Salute, University Magna Græcia, Campus “S. Venuta”, Catanzaro, Italy
3Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland
4Tecnologica Research Institute, Biomedical Section, Crotone, Italy
5Dipartimento di Biologia, Ecologia, Scienze Della Terra (DiBEST), Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Arcavacata di Rende, Italy
6Istituto di Endocrinologia e Oncologia Sperimentale, CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, University “Federico II” of Napoli, Napoli, Italy
Francesco Trapasso, email: [email protected]
Keywords: protein tyrosine phosphatase; PTPRJ; CD98hc; proteasomal degradation; lung cancer
Received: October 05, 2017 Accepted: March 24, 2018 Published: May 04, 2018
PTPRJ, a receptor protein tyrosine phosphatase strongly downregulated in human cancer, displays tumor suppressor activity by negatively modulating several proteins involved in proliferating signals. Here, through a proteomic-based approach, we identified a list of potential PTPRJ-interacting proteins and among them we focused on CD98hc, a type II glycosylated integral membrane protein encoded by SLC3A2, corresponding to the heavy chain of a heterodimeric transmembrane amino-acid transporter, including LAT1. CD98hc is widely overexpressed in several types of cancers and contributes to the process of tumorigenesis by interfering with cell proliferation, adhesion, and migration. We first validated PTPRJ-CD98hc interaction, then demonstrated that PTPRJ overexpression dramatically reduces CD98hc protein levels in A549 lung cancer cells. In addition, following to the treatment of PTPRJ-transduced cells with MG132, a proteasome inhibitor, CD98hc levels did not decrease compared to controls, indicating that PTPRJ is involved in the regulation of CD98hc proteasomal degradation. Moreover, PTPRJ overexpression combined with CD98hc silencing consistently reduced cell proliferation and triggered apoptosis of lung cancer cells. Interestingly, by interrogating the can Evolve database, we observed an inverse correlation between PTPRJ and SLC3A2 gene expression. Indeed, the non-small cell lung cancers (NSCLCs) of patients showing a short survival rate express the lowest and the highest levels of PTPRJ and SLC3A2, respectively. Therefore, the results reported here contribute to shed lights on PTPRJ signaling in cancer cells: moreover, our findings also support the development of a novel anticancer therapeutic approach by targeting the pathway of PTPRJ that is usually downregulated in highly malignant human neoplasias.
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