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Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex
F Vazquez1, S R Grossman, Y Takahashi
1Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
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.
Insights
Phosphorylation of the PTEN protein tail suppresses its tumor suppressor activity by altering its conformation. This change reduces PTEN
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Biology
Background:
- PTEN is a critical tumor suppressor protein.
- It antagonizes phosphoinositide 3-kinase signaling by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate.
- PTEN possesses distinct structural domains: N-terminal phosphatase, C2 lipid-binding, and a C-terminal tail with a PDZ binding motif.
Purpose of the Study:
- To investigate the regulatory role of PTEN tail phosphorylation on PTEN activity and protein interactions.
- To elucidate the conformational changes associated with PTEN tail phosphorylation.
- To understand how these changes affect PTEN's interaction with PDZ domain-containing proteins like MAGI-2.
Main Methods:
- Conformational analysis of phosphorylated and unphosphorylated PTEN.
- Assessment of PTEN's affinity for PDZ domain-containing proteins.
- Co-expression studies with PTEN mutants and MAGI-2 to evaluate Akt activation.
Main Results:
- Phosphorylation of the PTEN tail induces a monomeric, "closed" conformation with reduced affinity for PDZ proteins.
- Unphosphorylated PTEN adopts an "open" conformation, forms a high molecular weight complex, and binds strongly to MAGI-2.
- A phosphorylation-deficient PTEN mutant cooperates more effectively with MAGI-2 to inhibit Akt activation.
Conclusions:
- PTEN tail phosphorylation triggers a conformational shift that masks the PDZ binding domain.
- This masking significantly reduces PTEN's binding to PDZ-containing proteins.
- PTEN activity is suppressed by phosphorylation-induced changes in its recruitment into the PTEN-associated complex.