Acute regulation of the tumour suppressor phosphatase, PTEN, by anionic lipids and reactive oxygen species.
PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a member of the protein tyrosine phosphatase family that is structurally adapted to facilitate the metabolism of 3-phosphoinositide lipid second messengers, especially PtdIns(3,4,5) P (3). Cellular PTEN activity is restrained by the retention of C-terminally phosphorylated enzyme in the cytosol. Dephosphorylation by as yet undefined phosphatases initiates an electrostatic switch which targets PTEN specifically to the plasma membrane, where it binds through multiple positively charged residues in both the C2 and N-terminal domains and is susceptible to feedback regulation through proteolytic degradation. PTEN also forms signalling complexes with PDZ domain-containing adaptors, such as the MAGUK (membrane-associated guanylate kinase) proteins, interactions which appear to be necessary for metabolism of localized pools of PtdIns(3,4,5) P (3) involved in regulating actin cytoskeleton dynamics. TPIP [TPTE (transmembrane phosphatase with tensin homology) and PTEN homologous inositol lipid phosphatase] is a novel gene product which exists in multiply spliced forms. TPIPalpha has PtdIns(3,4,5) P (3) 3-phosphatase activity and is localized to the endoplasmic reticulum, via two transmembrane spanning regions, where it may metabolize PtdIns(3,4,5) P (3) that appears to be unaffected by expressed PTEN. PTEN can be acutely regulated by oxidative stress and by endogenously produced reactive oxygen species. This mechanism provides a novel means to stimulate phosphoinositide 3-kinase-dependent signalling pathways, which may be important in circumstances where PtdIns(3,4,5) P (3) and oxidants are produced concurrently.
Downes
C P
CP
Division of Cell Signalling, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee DD1 5EH, Scotland, U.K. c.p.downes@dundee.ac.uk
Walker
S
S
McConnachie
G
G
Lindsay
Y
Y
Batty
I H
IH
Leslie
N R
NR
D000595:Amino Acid Sequence; D000838:Anions; D001665:Binding Sites; D020134:Catalytic Domain; D003600:Cytosol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008969:Molecular Sequence Data; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000737:chemistry*
D000838:Anions; D008055:Lipids; D016877:Oxidants; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D010100:Oxygen