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The serine protease HtrA1 specifically interacts and degrades the tuberous sclerosis complex 2 protein

Campioni, Mara, Severino, Anna, Manente, Lucrezia, Tuduce, Ioana L., Toldo, Stefano, Caraglia, Michele, Crispi, Stefania, Ehrmann, Michael, He, Xiaoping, Maguire, Jacie, De Falco, Maria, De Luca, Antonia, Shridhar, Viji and Baldi, Alfonso 2010. The serine protease HtrA1 specifically interacts and degrades the tuberous sclerosis complex 2 protein. Molecular Cancer Research 8 (9) , pp. 1248-1260. 10.1158/1541-7786.MCR-09-0473

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Abstract

Hamartin and tuberin are products of the tumor suppressor genes TSC1 and TSC2, respectively. Mutations affecting either gene result in the tuberous sclerosis syndrome, a neurologic genetic disorder characterized by the formation of multiple benign tumors or hamartomas. In this study, we report the identification of TSC2, but not TSC1, as a substrate of HtrA1, a member of the human HtrA family proteins of serine proteases. We show the direct interaction and colocalization in the cytoplasm of HtrA1 and TSC2 and that HtrA1 cleaves TSC2 both in vitro and in vivo. Finally, we show that alterations in HtrA1 expression cause modifications in phosphorylation status of two downstream targets of TSC2: 4E-BP1 and S6K. Our data suggest that, under particular physiologic or pathologic conditions, HtrA1 degrades TSC2 and activates the downstream targets. Considering that HtrA1 levels are significantly increased during embryogenesis, we speculate that one of the targets of HtrA1 activity during fetal development is the TSC2-TSC1 pathway.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Association for Cancer Research
ISSN: 1541-7786
Last Modified: 04 Jun 2017 06:10
URI: http://orca.cf.ac.uk/id/eprint/56935

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