Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases.
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.
Valiente
Miguel
M
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.
Andrés-Pons
Amparo
A
Gomar
Beatriz
B
Torres
Josema
J
Gil
Anabel
A
Tapparel
Caroline
C
Antonarakis
Stylianos E
SE
Pulido
Rafael
R
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins; D000074288:Discs Large Homolog 1 Protein; D049029:Dystrophin-Associated Proteins / Q000737:chemistry*; D005982:Glutathione Transferase / Q000378:metabolism; D051528:Guanylate Kinases; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D049029:Dystrophin-Associated Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C084505:Mtssk protein, mouse; D011506:Proteins; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C091824:syntrophin; D005982:Glutathione Transferase; C503880:MAST2 protein, human; D017346:Protein Serine-Threonine Kinases; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; C485777:MAGI2 protein, human; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human