Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases

Miguel Valiente; Amparo Andrés-Pons; Beatriz Gomar; Josema Torres; Anabel Gil; Caroline Tapparel; Stylianos E Antonarakis; Rafael Pulido

doi:10.1074/jbc.M504761200

Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases

J Biol Chem. 2005 Aug 12;280(32):28936-43. doi: 10.1074/jbc.M504761200. Epub 2005 Jun 10.

Authors

Miguel Valiente¹, Amparo Andrés-Pons, Beatriz Gomar, Josema Torres, Anabel Gil, Caroline Tapparel, Stylianos E Antonarakis, Rafael Pulido

Affiliation

¹ Centro de Investigación Príncipe Felipe, Valencia 46013, Spain and Division of Medical Genetics, Centre Medical Universitaire, University of Geneva Medical School, 1 Rue Michel Servet, Geneva CH-1211, Switzerland.

PMID: 15951562
DOI: 10.1074/jbc.M504761200

Abstract

The tumor suppressor phosphatase PTEN is a key regulator of cell growth and apoptosis that interacts with PDZ domains from regulatory proteins, including MAGI-1/2/3, hDlg, and MAST205. Here we identified novel PTEN-binding PDZ domains within the MAST205-related proteins, syntrophin-associated serine/threonine kinase and MAST3, characterized the regions of PTEN involved in its interaction with distinctive PDZ domains, and analyzed the functional consequences on PTEN of PDZ domain binding. Using a panel of PTEN mutations, as well as PTEN chimeras containing distinct domains of the related protein TPTE, we found that the PTP and C2 domains of PTEN do not affect PDZ domain binding and that the C-terminal tail of PTEN (residues 350-403) provides selectivity to recognize specific PDZ domains from MAGI-2, hDlg, and MAST205. Binding of PTEN to the PDZ-2 domain from MAGI-2 increased PTEN protein stability. Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases. Our results suggest an important role for the C-terminal region of PTEN in the selective association with scaffolding and/or regulatory molecules and provide evidence that PDZ domain binding stabilizes PTEN and targets this tumor suppressor for phosphorylation by microtubule-associated serine/threonine kinases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Amino Acid Motifs
Animals
COS Cells
Carrier Proteins
Discs Large Homolog 1 Protein
Dystrophin-Associated Proteins / chemistry*
Glutathione Transferase / metabolism
Guanylate Kinases
Humans
Immunoprecipitation
Membrane Proteins
Microtubule-Associated Proteins / metabolism
Microtubules / metabolism*
Models, Biological
Mutation
Nucleoside-Phosphate Kinase / metabolism
PTEN Phosphohydrolase
Phosphoric Monoester Hydrolases / chemistry
Phosphoric Monoester Hydrolases / metabolism*
Phosphorylation
Plasmids / metabolism
Protein Binding
Protein Serine-Threonine Kinases / metabolism
Protein Structure, Tertiary
Proteins / metabolism
Recombinant Fusion Proteins / chemistry
Saccharomyces cerevisiae / metabolism
Time Factors
Transfection
Tumor Suppressor Proteins / chemistry
Tumor Suppressor Proteins / metabolism*
Two-Hybrid System Techniques

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
DLG1 protein, human
Discs Large Homolog 1 Protein
Dlg1 protein, mouse
Dystrophin-Associated Proteins
Membrane Proteins
Microtubule-Associated Proteins
Mtssk protein, mouse
Proteins
Recombinant Fusion Proteins
Tumor Suppressor Proteins
syntrophin
Glutathione Transferase
MAST2 protein, human
Protein Serine-Threonine Kinases
Nucleoside-Phosphate Kinase
Guanylate Kinases
MAGI2 protein, human
Phosphoric Monoester Hydrolases
PTEN Phosphohydrolase
PTEN protein, human