Negative feedback regulation of the tumor suppressor PTEN by phosphoinositide-induced serine phosphorylation.
The PTEN tumor suppressor phosphatase directly counteracts the multiple functions of phosphatidylinositol 3-kinase by removing phosphate from the D3 position of inositol phospholipids. Like many lymphomas and leukemias, the Jurkat T cell line lacks PTEN protein due to frame-shift mutations in both PTEN alleles and therefore survives in long-term cell culture. We report that PTEN reintroduced into Jurkat was highly phosphorylated on serines 380 and 385 in its C terminus, particularly the former site. Phosphate was also detected at Ser(380) in PTEN in untransformed human T cells. Treatments that reduced the levels of D3-phospholipids in the cells resulted in reduced phosphorylation and accelerated degradation of PTEN. In contrast, expression of inactive PTEN-C124G or coexpression of a constitutively active protein kinase B led to increased phosphorylation and slower degradation of PTEN. These results suggest that PTEN normally is subjected to a feedback mechanism of regulation aimed at maintaining homeostatic levels of D3-phosphoinositides, which are crucial for T cell survival and activation.
Birle
Diana
D
Program of Signal Transduction, Burnham Institute, La Jolla, CA 92037, USA.
Bottini
Nunzio
N
Williams
Scott
S
Huynh
Huong
H
deBelle
Ian
I
Adamson
Eileen
E
Mustelin
Tomas
T
D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005246:Feedback; D006207:Half-Life; D006801:Humans; D019169:Jurkat Cells / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D012694:Serine; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000409:Alanine