Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin.
Normal cellular functions of hamartin and tuberin, encoded by the TSC1 and TSC2 tumor suppressor genes, are closely related to their direct interactions. However, the regulation of the hamartin-tuberin complex in the context of the physiologic role as tumor suppressor genes has not been documented. Here we show that insulin or insulin growth factor (IGF) 1 stimulates phosphorylation of tuberin, which is inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the mitogen-activated protein kinase inhibitor PD98059. Expression of constitutively active PI3K or active Akt, including Akt1 and Akt2, induces tuberin phosphorylation. We further demonstrate that Akt/PKB associates with hamartin-tuberin complexes, promoting phosphorylation of tuberin and increased degradation of hamartin-tuberin complexes. The ability to form complexes, however, is not blocked. Akt also inhibits tuberin-mediated degradation of p27(kip1), thereby promoting CDK2 activity and cellular proliferation. Our results indicate that tuberin is a direct physiological substrate of Akt and that phosphorylation of tuberin by PI3K/Akt is a major mechanism controlling hamartin-tuberin function.
Dan
Han C
HC
Department of Pathology, Molecular Oncology, and Drug Discovery Programs, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA.
Sun
Mei
M
Yang
Lin
L
Feldman
Richard I
RI
Sui
Xue-Mei
XM
Ou
Chien Chen
CC
Nellist
Mark
M
Yeung
Raymond S
RS
Halley
Dicky J J
DJ
Nicosia
Santo V
SV
Pledger
Warren J
WJ
Cheng
Jin Q
JQ
D000595:Amino Acid Sequence; D000818:Animals; D001769:Blood; D002460:Cell Line; D016147:Genes, Tumor Suppressor; D006801:Humans; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624652:Tsc1 protein, rat; C000624655:Tsc2 protein, rat; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494920:Akt1 protein, rat; C494923:Akt2 protein, rat