OnlineFirst on August 24 , 2010 Molecular Cancer esearch aling and Regulation Serine Protease HtrA 1 Specifically Interacts and R rades the Tuberous Sclerosis Complex 2 Protein

ownload artin and tuberin are products of the tumor suppressor genes TSC1 and TSC2, respectively. Mutations ng either gene result in the tuberous sclerosis syndrome, a neurologic genetic disorder characterized by rmation of multiple benign tumors or hamartomas. In this study, we report the identification of TSC2, t TSC1, as a substrate of HtrA1, a member of the human HtrA family proteins of serine proteases. ow the direct interaction and colocalization in the cytoplasm of HtrA1 and TSC2 and that HtrA1 cleaves both in vitro and in vivo. Finally, we show that alterations in HtrA1 expression cause modifications in phosation status of two downstream targets of TSC2: 4E-BP1 and S6K. Our data suggest that, under particular logic or pathologic conditions, HtrA1 degrades TSC2 and activates the downstream targets. Considering physio 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. Mol Cancer Res; 8(9); OF1–13. ©2010 AACR.