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Titolo:
Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions
Autore:
Leslie, NR; Bennett, D; Gray, A; Pass, I; Hoang-Xuan, K; Downes, CP;
Indirizzi:
Univ Dundee, Dept Biochem, Div Signal Transduct Therapy, Dundee DD1 5EH, Scotland Univ Dundee Dundee Scotland DD1 5EH ct Therapy, Dundee DD1 5EH, Scotland Hop La Pitie Salpetriere, Neurol Clin, Paris, France Hop La Pitie Salpetriere Paris France riere, Neurol Clin, Paris, France Hop La Pitie Salpetriere, INSERM, U495, Paris, France Hop La Pitie Salpetriere Paris France iere, INSERM, U495, Paris, France
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 357, anno: 2001,
parte:, 2
pagine: 427 - 435
SICI:
0264-6021(20010715)357:<427:TMOPRD>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-B; LIPID PHOSPHATASE-ACTIVITY; CELL-CYCLE ARREST; PHOSPHOINOSITIDE 3-KINASE; GLIOBLASTOMA CELLS; SIGNALING PATHWAY; PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE; PHOSPHOLIPID PHOSPHATASE; PDZ DOMAIN; ACTIVATION;
Keywords:
glioblastoma; PDZ domains; phosphatase; phosphoinositide; protein kinase B;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Leslie, NR Univ Dundee, Dept Biochem, Div Signal Transduct Therapy, DundeeDD1 5EH, Scotland Univ Dundee Dundee Scotland DD1 5EH Dundee DD1 5EH, Scotland
Citazione:
N.R. Leslie et al., "Targeting mutants of PTEN reveal distinct subsets of tumour suppressor functions", BIOCHEM J, 357, 2001, pp. 427-435

Abstract

The tumour suppressor protein PTEN (phosphatase and tensin homolog deletedon chromosome 10) is a lipid phosphatase which can antagonize the phosphoinositide 3-kinase (PI 3-kinase) signalling pathway, promoting apoptosis andinhibiting 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)P-3 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. Thedata 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 carryinga 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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Documento generato il 16/07/20 alle ore 19:20:43