TY - JOUR
T1 - Rhomboid-Like-2 Intramembrane Protease Mediates Metalloprotease-Independent Regulation of Cadherins
AU - Battistini, Chiara
AU - Rehman, Michael
AU - Avolio, Marco
AU - Arduin, Alessia
AU - Valdembri, Donatella
AU - Serini, Guido
AU - Tamagnone, Luca
PY - 2019
Y1 - 2019
N2 - 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 TNF. The E-cadherin extracellular domain is known to be released by metalloproteases (MMPs); however, here, we provide evidence of a novel MMP-independent, TNF inducible, E-cadherin processing mechanism that is mediated by RHBDL2. Thus, the intramembrane protease RHBDL2 is a novel regulator of cadherins promoting cell motility.
AB - 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 TNF. The E-cadherin extracellular domain is known to be released by metalloproteases (MMPs); however, here, we provide evidence of a novel MMP-independent, TNF inducible, E-cadherin processing mechanism that is mediated by RHBDL2. Thus, the intramembrane protease RHBDL2 is a novel regulator of cadherins promoting cell motility.
KW - E-cadherin
KW - Rhomboid E-cadherin
KW - cell migration
KW - proteolytic cleavage
KW - E-cadherin
KW - Rhomboid E-cadherin
KW - cell migration
KW - proteolytic cleavage
UR - http://hdl.handle.net/10807/144194
U2 - 10.3390/ijms20235958
DO - 10.3390/ijms20235958
M3 - Article
SN - 1422-0067
VL - 20
SP - 1
EP - 17
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
ER -