Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions

The tumour suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase which can antagonize the phosphoinositide 3-kinase (PI 3-kinase) signalling pathway, promoting apoptosis and inhibiting cell-cycle progression and cell motility. We show that very litt...

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Bibliographic Details
Published in:Biochemical journal 2001-07, Vol.357 (Pt 2), p.427-435
Main Authors: Leslie, N R, Bennett, D, Gray, A, Pass, I, Hoang-Xuan, K, Downes, C P
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Adhesion
Cell Line
Cell Movement
Chromosomes, Human, Pair 10
DNA Primers
Genes, Tumor Suppressor
Humans
Inositol - metabolism
Kinetics
Molecular Sequence Data
Mutagenesis, Site-Directed
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphoric Monoester Hydrolases - chemistry
Phosphoric Monoester Hydrolases - genetics
Phosphoric Monoester Hydrolases - metabolism
Polymerase Chain Reaction
protein kinase B
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
PTEN gene
PTEN Phosphohydrolase
Recombinant Fusion Proteins - metabolism
Signal Transduction
Transfection
Tumor Suppressor Proteins
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Summary:The tumour suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase which can antagonize the phosphoinositide 3-kinase (PI 3-kinase) signalling pathway, promoting apoptosis and inhibiting cell-cycle progression and cell motility. We show that very little cellular PTEN is associated with the plasma membrane, but that artificial membrane-targeting of PTEN enhances its inhibition of signalling to protein kinase B (PKB). Evidence for potential targeting of PTEN to the membrane through PDZ domain-mediated protein-protein interactions led us to use a PTEN enzyme with a deletion of the C-terminal PDZ-binding sequence, that retains full phosphatase activity against soluble substrates, and to analyse the efficiency of this mutant in different cellular assays. The extreme C-terminal PDZ-binding sequence was dispensable for the efficient down-regulation of cellular PtdIns(3,4,5)P3 levels and a number of PI 3-kinase-dependent signalling activities, including PKB and p70S6K. However, the PDZ-binding sequence was required for the efficient inhibition of cell spreading. The data show that a PTEN mutation, similar to those found in some tumours, affects some functions of the protein but not others, and implicate the deregulation of PTEN-dependent processes other than PKB activation in the development of some tumours. Significantly, this hypothesis is supported by data showing low levels of PKB phosphorylation in a glioblastoma sample carrying a mutation in the extreme C-terminus of PTEN compared with tumours carrying phosphatase-inactivating mutations of the enzyme. Our data show that deregulation of PKB is not a universal feature of tumours carrying PTEN mutations and implicate other processes that may be deregulated in these tumours.
ISSN:0264-6021
1470-8728
DOI:10.1042/0264-6021:3570427