RGD Reference Report - 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.

General

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.
Authors:	Xiao, Yi Yeong Chit Chia, Joel Gajewski, Joanna E Sio Seng Lio, Daisy Mulhern, Terrence D Zhu, Hong-Jian Nandurkar, Harshal Cheng, Heung-Chin
Citation:	Xiao Y, etal., Cell Signal. 2007 Jul;19(7):1434-45. Epub 2007 Jan 25.
RGD ID:	12802336
Pubmed:	PMID:17324556 (View Abstract at PubMed)
DOI:	DOI:10.1016/j.cellsig.2007.01.021 (Journal Full-text)
PTEN exerts its tumour suppressor function by dephosphorylating the phospholipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP(3)). Herein, we demonstrate that the PTEN-catalysed PIP(3) 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.

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Biological Process

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
phosphatidylinositol dephosphorylation		IDA		12802336		RGD

Molecular Function

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity		IDA		12802336		RGD

Objects Annotated

Genes (Rattus norvegicus)

Pten (phosphatase and tensin homolog)

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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.