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

Chiara Battistini,Marco Avolio,Guido Serini,Michael Rehman,Donatella Valdembri,Alessia Arduin,Luca Tamagnone

doi:10.3390/ijms20235958

Abstract

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.

Highlights

Cell regulation is largely due to molecules that are localized at the plasma membrane
In a high throughput functional screening in PC3 prostate carcinoma cells, the knock-down of intramembrane protease gene RHBDL2 was serendipitously found to inhibit cell migration. This was consistent with data that were shown in a previous study on normal keratinocytes [24]; the potential relevance of this protease in cancer cell migration had not been formerly investigated
We decided to focus on RHBDL2 by performing new independent gene silencing experiments in the PC3 cells, and confirming its functional relevance in another invasive cancer cell line, the triple-negative breast carcinoma cells MDA-MB468 characterized by a high expression of the protease (Figure S1A,B and Figure 1A,B)

Summary

Introduction

Cell regulation is largely due to molecules that are localized at the plasma membrane. They mostly include receptors for extracellular signals, transporters, and adhesive proteins. E-cadherin, which is mainly expressed in epithelial cells, is known to have additional functions beyond establishing stable cell–cell contacts, by controlling cell signaling cascades driving cell differentiation, proliferation/self-renewal, and cell migration [5,6]. Its surface expression appears to be relevant in carcinoma cells that are not engaged in cell-cell contacts, which suggests that its function goes beyond stabilizing the quiescent epithelial cell layers [7,8,9]

Methods

Results

Conclusion