title: The C-terminal tail inhibitory phosphorylation sites of PTEN regulate its intrinsic catalytic activity and the kinetics of its binding to phosphatidylinositol-4,5-bisphosphate.
abstract: Dephosphorylation of four major C-terminal tail sites and occupancy of the phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]-binding site of PTEN cooperate to activate its phospholipid phosphatase activity and facilitate its recruitment to plasma membrane. Our investigation of the mechanism by which phosphorylation of these C-terminal sites controls the PI(4,5)P2-binding affinity and catalytic activity of PTEN resulted in the following findings. First, dephosphorylation of all four sites leads to full activation; and phosphorylation of any one site significantly reduces the intrinsic catalytic activity of PTEN. These findings suggest that coordinated inhibition of the upstream protein kinases and activation of the protein phosphatases targeting the four sites are needed to fully activate PTEN phosphatase activity. Second, PI(4,5)P2 cannot activate the phosphopeptide phosphatase activity of PTEN, suggesting that PI(4,5)P2 can only activate the phospholipid phosphatase activity but not the phosphoprotein phosphatase activity of PTEN. Third, dephosphorylation of all four sites significantly decreases the affinity of PTEN for PI(4,5)P2. Since PI(4,5)P2 is a major phospholipid co-localizing with the phospholipid- and phosphoprotein-substrates in plasma membrane, we hypothesise that the reduced affinity facilitates PTEN to "hop" on the plasma membrane to dephosphorylate these substrates.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Yeong-Chit Joel
authors.initials: YC
authors.lastname: Chia
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Bruno
authors.initials: B
authors.lastname: Catimel
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Daisy Sio Seng
authors.initials: DS
authors.lastname: Lio
authors.affiliation: Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Ching-Seng
authors.initials: CS
authors.lastname: Ang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Peng
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: heung@unimelb.edu.au.
authors.forename: Heung-Chin
authors.initials: HC
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004789:Enzyme Activation; D007700:Kinetics; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D018129:Phosphatidylinositol Phosphates; D011994:Recombinant Proteins; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat
keywords: C-terminal tail; Kinetics; PTEN; Phosphatase; Phosphatidylinositol-4,5-bisphosphate; Phosphorylation