Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex.

PTEN is a tumor suppressor protein that functions, in large part, by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate and by doing so antagonizing the action of phosphoinositide 3-kinase. PTEN structural domains include an N-terminal phosphatase domain, a lipid-binding C2 domain, and a 50-amino acid C-terminal tail that contains a ...
PDZ binding sequence. We showed previously that phosphorylation of the PTEN tail negatively regulates PTEN activity. We now show that phosphorylated PTEN exists in a monomeric "closed" conformation and has low affinity for PDZ domain-containing proteins. Conversely, when unphosphorylated, PTEN is in an "open" conformation, is recruited into a high molecular weight complex (PTEN-associated complex), and strongly interacts with PDZ-containing proteins such as MAGI-2. As a consequence, when compared with wild-type PTEN, the phosphorylation-deficient mutant form of PTEN strongly cooperates with MAGI-2 to block Akt activation. These results indicate that phosphorylation of the PTEN tail causes a conformational change that results in the masking of the PDZ binding domain. Consequently, the ability of PTEN to bind to PDZ domain-containing proteins is reduced dramatically. These data suggest that phosphorylation of the PTEN tail suppresses the activity of PTEN by controlling the recruitment of PTEN into the PTEN-associated complex.
Mesh Terms:
Activin Receptors, Type II, Animals, Carrier Proteins, Cell Line, Guanylate Kinases, Humans, Isoenzymes, Models, Biological, Multienzyme Complexes, Nucleoside-Phosphate Kinase, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases, Phosphorylation, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Rats, Tumor Suppressor Proteins
J. Biol. Chem.
Date: Dec. 28, 2001
Download Curated Data For This Publication
215244
Switch View:
  • Interactions 3