Regulation of PTEN Phosphorylation and Stability by a Tumor Suppressor Candidate Protein

• Published in: The Journal of biological chemistry 2004-10, Vol.279 (44), p.45300-45303
• Main Authors: Okahara, Fumiaki, Ikawa, Hideki, Kanaho, Yasunori, Maehama, Tomohiko
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Humans; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; PTEN Phosphohydrolase; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C400377200

The tumor suppressor PTEN plays an essential role in regulating signaling pathways involved in cell growth and apoptosis and is inactivated in a wide variety of tumors. In this study, we have identified a protein, referred to as PICT-1 ( p rotein i nteracting with c arboxyl t erminus 1 ), that binds to the C terminus of PTEN and regulates its phosphorylation and turnover. Down-regulation of PICT-1 in MCF7 cells by RNA interference enhances the degradation of PTEN with a concomitant decrease in its phosphorylation. PTEN C-terminal tumor-associated mutants, which are highly susceptible to protein degradation, have lost the ability to bind to PICT-1 along with their reduced phosphorylation, suggesting that their rapid turnover results from impaired binding to PICT-1. Our results identify PICT-1 as a PTEN-interacting protein that promotes the phosphorylation and stability of PTEN. These findings suggest a novel molecular mechanism underlying the turnover of PTEN, which also provides an explanation for the loss of PTEN function due to C-terminal mutations.