PTEN catalysis of phospholipid dephosphorylation reaction follows a two-step mechanism in which the conserved aspartate-92 does not function as the general acid - Mechanistic analysis of a familial Cowden disease-associated PTEN mutation

Yi Xiao, Joel Yeong Chit Chia, Joanna E Gajewski, Daisy Sio Seng Lio, Terrence Damian Mulhern, Hong-Jian Zhu, Harshal Hanumant Nandurkar, Heung-Chin Cheng

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

PTEN exerts its tumour suppressor function by dephosphorylating the phospholipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3). Herein, we demonstrate that the PTEN-catalysed PIP3 dephosphorylation reaction involves two-steps: (i) formation of a phosphoenzyme intermediate (PE) in which Cys-124 in the active site is thiophosphorylated, and (ii) hydrolysis of PE. For protein tyrosine- and dual-specificity phosphatases, catalysis requires the participation of a conserved active site aspartate as the general acid in Step 1. Its mutation to alanine severely limits PE formation. However, mutation of the homologous Asp-92 in PTEN does not significantly limit PE formation, indicating that Asp-92 does not act as the general acid. G129E is a common germline PTEN mutations found in Cowden syndrome patients. Mechanistic analysis reveals that this mutation inactivates PTEN by both significantly slowing down Step 1 and abolishing the ability to catalyse Step 2. Taken together, our results highlight the mechanistic similarities and differences between PTEN and the conventional protein phosphatases and reveal how a disease-associated mutation inactivates PTEN.
Original languageEnglish
Pages (from-to)1434 - 1442
Number of pages9
JournalCellular Signalling
Volume19
Issue number7
DOIs
Publication statusPublished - 2007
Externally publishedYes

Cite this