Abstract:
:Protein Kinase B (PKB/Akt) is a key regulator of cell proliferation, motility and survival. The activation status of PKB is regulated by phosphatidylinositol 3-kinase (PI3K) via the synthesis of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3, PIP3). PTEN antagonises PI3K by degrading PIP3 to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). Deregulation of PKB through loss of functional PTEN has frequently been implicated in the progression of tumours, including prostate cancer, and the PTEN-negative prostate cancer cell lines LNCaP and PC3 have been widely used as models for this mechanism of constitutive PKB activation. However, other enzymes in addition to PTEN can antagonise PI3K, including SHIP2, which degrades PIP3 to phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2). We investigated the role of PTEN and SHIP2 in the regulation of PKB phosphorylation in a panel of human prostate-derived epithelial cell lines. In the PTEN-positive prostate-derived cell lines PNT2, PNT1a and P4E6, PI3K inhibition by LY294002 caused rapid dephosphorylation of PKB at ser473 (T(1/2)<2 min), leading to its inactivation. In the PTEN-null line LNCaP, LY294002-induced PKB dephosphorylation was much slower (T(1/2)>20 min), but in PC3 cells (also PTEN-null) it was only slightly slower than in PTEN-positive cells (T(1/2)=3 min). PKB dephosphorylation paralleled loss of plasma membrane PIP3. PNT1a, P4E6 and PC3, but not PNT2 or LNCaP, expressed SHIP2. SiRNA-mediated knockdown of SHIP2 expression markedly slowed PKB inactivation in response to LY294002 in PC3 but not in other SHIP2-positive cells, whereas knockdown of PTEN expression in PNT2, PNT1a and P4E6 resulted in higher steady-state levels of PKB phosphorylation and slowed, but did not prevent, LY294002-induced PKB inactivation. Thus SHIP2 substitutes for PTEN in the acute regulation of PKB in PC3 cells but not other prostate cell lines, where PTEN may share this role with further PIP3-degrading mechanisms.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
Sharrard RM,Maitland NJdoi
10.1016/j.cellsig.2006.05.029subject
Has Abstractpub_date
2007-01-01 00:00:00pages
129-38issue
1eissn
0898-6568issn
1873-3913pii
S0898-6568(06)00143-4journal_volume
19pub_type
杂志文章abstract::In eukaryotes, proper loading and activation of MCM helicase at chromosomal origins plays a central role in DNA replication. Activation of MCM helicase requires its association with CDC45-GINS complex, but the mechanism of how this complex activates MCM helicase is poorly understood. Here we identified SIK1 (salt-indu...
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2006.07.018
更新日期:2006-11-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章,评审
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journal_title:Cellular signalling
pub_type: 杂志文章
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journal_title:Cellular signalling
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doi:10.1016/0898-6568(89)90016-8
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journal_title:Cellular signalling
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2010.12.008
更新日期:2011-04-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2006.05.004
更新日期:2006-12-01 00:00:00
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journal_title:Cellular signalling
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更新日期:2002-09-01 00:00:00
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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