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| Subject Categories: Signal Transduction |
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| The EMBO Journal
(2007) 26, 3050–3061, doi:10.1038/sj.emboj.7601763 Published online 21 June 2007 |
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The p110 isoform of PI 3-kinase negatively controls RhoA and PTEN |
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| Evangelia A Papakonstanti1, Anne J Ridley1, 2 and Bart Vanhaesebroeck1, 2 |
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1 Ludwig Institute for Cancer Research, London, UK 2 Department of Biochemistry and Molecular Biology, University College London, London, UK To whom correspondence should be addressed Bart Vanhaesebroeck, Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK. Tel.: +44 207 878 4066; Fax: +44 207 878 4040; E-mail: bartvanh@ludwig.ucl.ac.uk Received 22 January 2007; Accepted 23 May 2007; Published online 21 June 2007. |
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| Abstract |
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| Inactivation of PI 3-kinase (PI3K) signalling is critical for tumour suppression by PTEN. This is thought to be a unidirectional relationship in which PTEN degrades the lipids produced by PI3K, thus controlling cell proliferation, survival and migration. We now show that this relationship is in fact bidirectional, whereby PI3K reciprocally controls PTEN. We report that the p110 PI3K negatively regulates PTEN, through a pathway involving inhibition of RhoA. Inactivation of p110 in macrophages led to reduced Akt and Rac1 activation, but paradoxically to increased RhoA and PTEN activity. Partial inactivation of p190RhoGAP and a reduced binding of cytoplasmic RhoA to the cyclin-dependent kinase inhibitor p27 both contributed to the increased RhoA-GTP levels upon p110 inactivation. Pharmacological inhibition of ROCK, a downstream effector kinase of RhoA, restored all signalling and functional defects of p110 inactivation, including Akt phosphorylation, chemotaxis and proliferation. This work identifies the RhoA/ROCK pathway as a major target of p110-mediated PI3K signalling, and establishes for the first time that PI3K controls itself, via a feedback loop involving PTEN. |
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| Keywords: p110 PI 3-kinase, PTEN, RhoA, ROCK, small GTPase |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSNature Cell Biology News and Views (01 Apr 2005) PTEN gives neutrophils direction Nature Immunology News and Views (01 Jul 2008) RESEARCHThe p110δ isoform of PI 3-kinase negatively controls RhoA and PTEN The EMBO Journal Article Regulation of PTEN by Rho small GTPases Nature Cell Biology Letter (01 Apr 2005) |
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