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 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.
Mesh Terms:
Animals, Base Sequence, Cell Adhesion, Cell Line, Cell Movement, Chromosomes, Human, Pair 10, DNA Primers, Genes, Tumor Suppressor, Humans, Inositol, Kinetics, Molecular Sequence Data, Mutagenesis, Site-Directed, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphoric Monoester Hydrolases, Polymerase Chain Reaction, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Recombinant Fusion Proteins, Signal Transduction, Transfection, Tumor Suppressor Proteins
Animals, Base Sequence, Cell Adhesion, Cell Line, Cell Movement, Chromosomes, Human, Pair 10, DNA Primers, Genes, Tumor Suppressor, Humans, Inositol, Kinetics, Molecular Sequence Data, Mutagenesis, Site-Directed, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphoric Monoester Hydrolases, Polymerase Chain Reaction, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Recombinant Fusion Proteins, Signal Transduction, Transfection, Tumor Suppressor Proteins
Biochem. J.
Date: Jul. 15, 2001
PubMed ID: 11439092
View in: Pubmed Google Scholar
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