The serine protease HtrA1 specifically interacts and degrades the tuberous sclerosis complex 2 protein.
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.
Campioni
Mara
M
Department of Biochemistry, Section of Pathology, Second University of Naples, Via L. Armanni 5, 80138 Naples, Italy.
Severino
Anna
A
Manente
Lucrezia
L
Tuduce
Ioana L
IL
Toldo
Stefano
S
Caraglia
Michele
M
Crispi
Stefania
S
Ehrmann
Michael
M
He
Xiaoping
X
Maguire
Jacie
J
De Falco
Maria
M
De Luca
Antonio
A
Shridhar
Viji
V
Baldi
Alfonso
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002999:Clone Cells; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D047468:Immunoprecipitation; D050505:Mutant Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000201:enzymology / Q000648:ultrastructure; D011247:Pregnancy; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D050505:Mutant Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D019893:Ribosomal Protein S6 Kinases; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases