Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions

Nick R Leslie, Deborah Bennett, Alexander Gray, Ian Pass, Khe Hoang-Xuan, C Peter Downes

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)427-435
Number of pages9
JournalBiochemical Journal
Volume357
Issue number2
Publication statusPublished - 15 Jul 2001

Keywords

  • 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

Fingerprint Dive into the research topics of 'Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions'. Together they form a unique fingerprint.

  • Cite this

    Leslie, N. R., Bennett, D., Gray, A., Pass, I., Hoang-Xuan, K., & Downes, C. P. (2001). Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions. Biochemical Journal, 357(2), 427-435.