Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 587, Issue -, Pages 48-60Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2015.10.004
Keywords
PTEN; C-terminal tail; Phosphorylation; Phosphatase; Phosphatidylinositol-4,5-bisphosphate; Kinetics
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Funding
- National Health and Medical Research Council of Australia [APP1050486]
- Australian Research Council
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Dephosphorylation of four major C-terminal tail sites and occupancy of the phosphatidylinositol-4,5-bisphosphate [PI(4,5)P-2]-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)P-2-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)P-2 cannot activate the phosphopeptide phosphatase activity of PTEN, suggesting that PI(4,5)P-2 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)P-2. Since PI(4,5)P-2 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. (C) 2015 Elsevier Inc. All rights reserved.
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