Abstract:
:We employ a novel, dominant negative approach to identify a key role for certain tethered cyclic AMP specific phosphodiesterase-4 (PDE4) isoforms in regulating cyclic AMP dependent protein kinase A (PKA) sub-populations in resting COS1 cells. A fraction of PKA is clearly active in resting COS1 cells and this activity increases when cells are treated with the selective PDE4 inhibitor, rolipram. Point mutation of a critical, conserved aspartate residue in the catalytic site of long PDE4A4, PDE4B1, PDE4C2 and PDE4D3 isoforms renders them catalytically inactive. Overexpressed in resting COS1 cells, catalytically inactive forms of PDE4C2 and PDE4D3, but not PDE4A4 and PDE4B1, are constitutively PKA phosphorylated while overexpressed active versions of all these isoforms are not. Inactive and active versions of all these isoforms are PKA phosphorylated in cells where protein kinase A is maximally activated with forskolin and IBMX. By contrast, rolipram challenge of COS1 cells selectively triggers the PKA phosphorylation of recombinant, active PDE4D3 and PDE4C2 but not recombinant, active PDE4A4 and PDE4B1. Purified, recombinant PDE4D3 and PDE4A4 show a similar dose-dependency for in vitro phosphorylation by PKA. Disruption of the tethering of PKA type-II to PKA anchor proteins (AKAPs), achieved using the peptide Ht31, prevents inactive forms of PDE4C2 and PDE4D3 being constitutively PKA phosphorylated in resting cells as does siRNA-mediated knockdown of PKA-RII, but not PKA-RI. PDE4C2 and PDE4D3 co-immunoprecipitate from COS1 cell lysates with 250 kDa and 450 kDa AKAPs that tether PKA type-II and not PKA type-I. PKA type-II co-localises with AKAP450 in the centrosomal region of COS1 cells. The perinuclear distribution of recombinant, inactive PDE4D3, but not inactive PDE4A4, overlaps with AKAP450 and PKA type-II. The distribution of PKA phosphorylated inactive PDE4D3 also overlaps with that of AKAP450 in the centrosomal region of COS1 cells. We propose that a novel role for PDE4D3 and PDE4C2 is to gate the activation of AKAP450-tethered PKA type-II localised in the perinuclear region under conditions of basal cAMP generation in resting cells.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
McCahill A,McSorley T,Huston E,Hill EV,Lynch MJ,Gall I,Keryer G,Lygren B,Tasken K,van Heeke G,Houslay MDdoi
10.1016/j.cellsig.2005.04.003subject
Has Abstractpub_date
2005-09-01 00:00:00pages
1158-73issue
9eissn
0898-6568issn
1873-3913pii
S0898-6568(05)00083-5journal_volume
17pub_type
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2013.08.016
更新日期:2013-12-01 00:00:00
abstract:PURPOSE OF REVIEW:microRNAs (miRNAs) are a class of small, evolutionarily conserved, non-coding RNAs (ncRNAs) that function as inhibitors of post-transcriptional mRNA expression. They are implicated in the pathogenesis of numerous diseases, including many common kidney conditions. In this review, we focus on how miRNAs...
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doi:10.1016/0898-6568(90)90050-k
更新日期:1990-01-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
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abstract::Signal transducer and activator of transcription 6 (Stat6) is critical in Th2 polarization of immune cells and active Stat6 activity has been suggested in anti-tumor immunity in animal models. The present study aims at investigating the impact of natural Stat6 activity on tumor microenvironment in human colorectal can...
journal_title:Cellular signalling
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doi:10.1016/j.cellsig.2011.11.005
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abstract::The dual-specificity mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) inactivates MAP kinases by dephosphorylation. Here we show that the proinflammatory cytokine interleukin (IL)-17A induces adult mouse primary cardiac fibroblast (CF) proliferation and migration via IL-17 receptor A//IL-17 receptor C-dep...
journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2011.10.010
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2011.12.001
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pub_type: 杂志文章
doi:10.1016/s0898-6568(01)00268-6
更新日期:2002-04-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2018.03.010
更新日期:2018-07-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2011.01.013
更新日期:2011-05-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2009.07.003
更新日期:2009-11-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/0898-6568(93)90080-6
更新日期:1993-07-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2004.10.015
更新日期:2005-06-01 00:00:00
abstract:PURPOSE:Our study aimed to study the role of lncRNA TP73-AS1/miR-539/MMP-8 axis in modulating M2 macrophage polarization in hepatocellular carcinoma (HCC). METHODS:The gene expression levels of TP73-AS1, miR-539 and MMP-8 were modified by transfection with the overexpression or knockdown vectors. The patient survival ...
journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2020.109738
更新日期:2020-11-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2014.02.006
更新日期:2014-06-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2008.03.009
更新日期:2008-07-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/s0898-6568(02)00017-7
更新日期:2002-09-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章,评审
doi:10.1016/j.cellsig.2011.12.009
更新日期:2012-04-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2008.10.014
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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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journal_title:Cellular signalling
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更新日期:2020-10-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/0898-6568(95)02017-9
更新日期:1996-01-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/s0898-6568(01)00247-9
更新日期:2002-02-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2007.06.007
更新日期:2007-11-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2005.08.019
更新日期:2006-07-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
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更新日期:1994-11-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/0898-6568(91)90037-u
更新日期:1991-01-01 00:00:00
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journal_title:Cellular signalling
pub_type: 杂志文章
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2016.02.011
更新日期:2016-05-01 00:00:00