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.
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July 2001
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Research Article|
July 09 2001
Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions
Nick R. LESLIE;
Nick R. LESLIE
1
∗Division of Signal Transduction Therapy, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
1To whom correspondence should be addressed (e-mail n.r.leslie@dundee.ac.uk).
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Deborah BENNETT;
Deborah BENNETT
∗Division of Signal Transduction Therapy, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Alex GRAY;
Alex GRAY
∗Division of Signal Transduction Therapy, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Ian PASS;
Ian PASS
∗Division of Signal Transduction Therapy, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Khe HOANG-XUAN;
Khe HOANG-XUAN
†Clinique Neurologique et INSERM U495, Hôpital de la Pitié-Salpêtrière, Paris, France
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C. Peter DOWNES
C. Peter DOWNES
∗Division of Signal Transduction Therapy, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Publisher: Portland Press Ltd
Received:
March 19 2001
Revision Received:
May 03 2001
Accepted:
May 14 2001
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2001
2001
Biochem J (2001) 357 (2): 427–435.
Article history
Received:
March 19 2001
Revision Received:
May 03 2001
Accepted:
May 14 2001
Citation
Nick R. LESLIE, Deborah BENNETT, Alex GRAY, Ian PASS, Khe HOANG-XUAN, C. Peter DOWNES; Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions. Biochem J 15 July 2001; 357 (2): 427–435. doi: https://doi.org/10.1042/bj3570427
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