Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration.
Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome characterized by seizures, mental retardation, autism, and tumors of the brain, kidney, heart, retina, and skin. TSC is caused by mutations in either TSC1 or TSC2, both of which are tumor suppressor genes. Hamartin, the protein product of TSC1, was found to interact with the ezrin-radixin-moesin family of cytoskeletal proteins and to activate the small GTPase Rho. To determine whether tuberin, the TSC2 product, can also activate Rho, we stably expressed full-length human tuberin in two cell types: MDCK cells and ELT3 cells. ELT3 cells lack endogenous tuberin expression. We found that expression of human tuberin in both MDCK and ELT3 cells was associated with an increase in the amount of Rho-GTP, but not in Rac1-GTP or cdc42-GTP. Tuberin expression increased cell adhesion in both cell types, and decreased chemotactic cell migration in ELT3 cells. In MDCK cells, there was a decrease in the amount of total Focal Adhesion Kinase (FAK) and an increase in the fraction of phosphorylated FAK. These findings demonstrate for the first time that tuberin activates Rho and regulates cell adhesion and migration. Pathways involving Rho activation may have relevance to the clinical manifestations of TSC, including pulmonary lymphangioleiomyomatosis.
Astrinidis
Aristotelis
A
Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania, PA 19111, USA.
Cash
Timothy P
TP
Hunter
Deborah S
DS
Walker
Cheryl L
CL
Chernoff
Jonathan
J
Henske
Elizabeth P
EP
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D011506:Proteins / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics*; D014162:Transfection; D014402:Tuberous Sclerosis / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D011506:Proteins; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624652:Tsc1 protein, rat; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins