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Open AccessArticle

Rhomboid-Like-2 Intramembrane Protease Mediates Metalloprotease-Independent Regulation of Cadherins

1
Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy
2
Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy
3
Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
4
Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy
*
Author to whom correspondence should be addressed.
Current address: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Int. J. Mol. Sci. 2019, 20(23), 5958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235958
Received: 13 November 2019 / Revised: 25 November 2019 / Accepted: 25 November 2019 / Published: 27 November 2019
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
Cadherins are a major family of cell–cell adhesive receptors, which are implicated in development, tissue homeostasis, and cancer. Here, we show a novel mechanism of post-translational regulation of E-cadherin in cancer cells by an intramembrane protease of the Rhomboid family, RHBDL2, which leads to the shedding of E-cadherin extracellular domain. In addition, our data indicate that RHBDL2 mediates a similar activity on VE-cadherin, which is selectively expressed by endothelial cells. We show that RHBDL2 promotes cell migration, which is consistent with its ability to interfere with the functional role of cadherins as negative regulators of motility; moreover, the two players appear to lie in the same functional pathway. Importantly, we show that RHBDL2 expression is induced by the inflammatory chemokine TNFα. The E-cadherin extracellular domain is known to be released by metalloproteases (MMPs); however, here, we provide evidence of a novel MMP-independent, TNFα inducible, E-cadherin processing mechanism that is mediated by RHBDL2. Thus, the intramembrane protease RHBDL2 is a novel regulator of cadherins promoting cell motility. View Full-Text
Keywords: rhomboid; E-cadherin; proteolytic cleavage; cell migration; TNFα rhomboid; E-cadherin; proteolytic cleavage; cell migration; TNFα
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MDPI and ACS Style

Battistini, C.; Rehman, M.; Avolio, M.; Arduin, A.; Valdembri, D.; Serini, G.; Tamagnone, L. Rhomboid-Like-2 Intramembrane Protease Mediates Metalloprotease-Independent Regulation of Cadherins. Int. J. Mol. Sci. 2019, 20, 5958. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235958

AMA Style

Battistini C, Rehman M, Avolio M, Arduin A, Valdembri D, Serini G, Tamagnone L. Rhomboid-Like-2 Intramembrane Protease Mediates Metalloprotease-Independent Regulation of Cadherins. International Journal of Molecular Sciences. 2019; 20(23):5958. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235958

Chicago/Turabian Style

Battistini, Chiara; Rehman, Michael; Avolio, Marco; Arduin, Alessia; Valdembri, Donatella; Serini, Guido; Tamagnone, Luca. 2019. "Rhomboid-Like-2 Intramembrane Protease Mediates Metalloprotease-Independent Regulation of Cadherins" Int. J. Mol. Sci. 20, no. 23: 5958. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235958

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