Synergy in tumor suppression by direct interaction of neutral endopeptidase with PTEN.
We show in this study that endogenous NEP and PTEN associate in cells directly through electrostatic interactions between a highly basic residue stretch in the intracellular domain of NEP and the major phosphorylation site in PTEN's tail. NEP binds and engages in higher order complexes both phosphorylated and unphosphorylated PTEN. NEP recruits PTEN to the plasma membrane and enhances its stability and phosphatase activity. As a result, an enzymatically inactive NEP mutant preserves the ability to bind PTEN, inactivates the Akt/PKB kinase, and partially suppresses the growth of PC cells. This study demonstrates a molecular cooperation between NEP and PTEN tumor suppressors in which NEP constitutively recruits and activates PTEN to inhibit the PI3K/Akt oncogenic pathway.
Sumitomo
Makoto
M
Urological Oncology Research Laboratory, Department of Urology, Joan and Stanford I Weill Medical College of Cornell University, New York, NY 10021, USA.
Iwase
Akira
A
Zheng
Rong
R
Navarro
Daniel
D
Kaminetzky
David
D
Shen
Ruoqian
R
Georgescu
Maria-Magdalena
MM
Nanus
David M
DM
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000201:enzymology; D002465:Cell Movement / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D015260:Neprilysin; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C494918:AKT1 protein, human