Akt phosphorylates and regulates Pdcd4 tumor suppressor protein.
Programmed cell death 4 (Pdcd4) is a tumor suppressor protein that interacts with eukaryotic initiation factor 4A and inhibits protein synthesis. Pdcd4 also suppresses the transactivation of activator protein-1 (AP-1)-responsive promoters by c-Jun. The Akt (protein kinase B) serine/threonine kinase is a key mediator of phosphoinositide 3-kinase pathway involved in the regulation of cell proliferation, survival, and growth. Because Pdcd4 has two putative Akt phosphorylation sites at Ser(67) and Ser(457), we investigated whether Akt phosphorylates and regulates Pdcd4. Our results show that Akt specifically phosphorylates Ser(67) and Ser(457) residues of Pdcd4 in vitro and in vivo. We further show that phosphorylation of Pdcd4 by Akt causes nuclear translocation of Pdcd4. Using luciferase assay, we show that phosphorylation of Pdcd4 by Akt also causes a significant decrease of the ability of Pdcd4 to interfere with the transactivation of AP-1-responsive promoter by c-Jun.
Palamarchuk
Alexey
A
Comprehensive Cancer Center, Human Cancer Genetics Program, and Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University School of Medicine, Columbus, 43210, USA.
Efanov
Alexey
A
Maximov
Vadim
V
Aqeilan
Rami I
RI
Croce
Carlo M
CM
Pekarsky
Yuri
Y
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation
D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; D016755:Proto-Oncogene Proteins c-jun; D016601:RNA-Binding Proteins; D018808:Transcription Factor AP-1; D012694:Serine; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt