Document Detail

Akt kinase phosphorylation of inositol 1,4,5-trisphosphate receptors.
MedLine Citation:
PMID:  16332683     Owner:  NLM     Status:  MEDLINE    
A consensus RXRXX(S/T) substrate motif for Akt kinase is conserved in the C-terminal tail of all three inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) isoforms. We have shown that IP3R can be phosphorylated by Akt kinase in vitro and in vivo. Endogenous IP3Rs in Chinese hamster ovary T-cells were phosphorylated in response to Akt activation by insulin. LnCAP cells, a prostate cancer cell line with constitutively active Akt kinase, also showed a constitutive phosphorylation of endogenous type I IP3Rs. In all cases, the IP3R phosphorylation was diminished by the addition of LY294002, an inhibitor of phosphatidylinositol 3-kinase. Mutation of IP3R serine 2681 in the Akt substrate motif to alanine (S2681A) or glutamate (S2681E) prevented IP3R phosphorylation in COS cells transfected with constitutively active Akt kinase. Analysis of the Ca2+ flux properties of these IP3R mutants expressed in COS cell microsomes or in DT40 triple knock-out (TKO) cells did not reveal any modification of channel function. However, staurosporine-induced caspase-3 activation in DT40 TKO cells stably expressing the S2681A mutant was markedly enhanced when compared with wild-type or S2681E IP3Rs. We conclude that IP3 receptors are in vivo substrates for Akt kinase and that phosphorylation of the IP3R may provide one mechanism to restrain the apoptotic effects of calcium.
M Tariq Khan; Larry Wagner; David I Yule; Cunnigaiper Bhanumathy; Suresh K Joseph
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2005-12-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-07     Completed Date:  2006-04-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3731-7     Citation Subset:  IM    
Department of Pathology and Cell Biology, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania 19107, USA.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / metabolism
Alanine / chemistry
Amino Acid Motifs
Amino Acid Sequence
CHO Cells
COS Cells
Calcium / metabolism
Calcium Channels / metabolism*
Calcium-Transporting ATPases / metabolism
Caspase 3
Caspases / metabolism
Cell Line
Cercopithecus aethiops
Chromones / pharmacology
DNA, Complementary / metabolism
Detergents / pharmacology
Enzyme Activation
Glutamic Acid / chemistry
Inositol 1,4,5-Trisphosphate Receptors
Microcirculation / metabolism
Molecular Sequence Data
Morpholines / pharmacology
Octoxynol / pharmacology
Proto-Oncogene Proteins c-akt / metabolism*
Receptors, Cytoplasmic and Nuclear / metabolism*
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Serine / chemistry
Staurosporine / pharmacology
Time Factors
Grant Support
Reg. No./Substance:
0/Calcium Channels; 0/Chromones; 0/DNA, Complementary; 0/Detergents; 0/ITPR1 protein, human; 0/Inositol 1,4,5-Trisphosphate Receptors; 0/Morpholines; 0/Receptors, Cytoplasmic and Nuclear; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 56-41-7/Alanine; 56-45-1/Serine; 56-86-0/Glutamic Acid; 62996-74-1/Staurosporine; 7440-70-2/Calcium; 9002-93-1/Octoxynol; EC 3-Kinase; EC Proteins c-akt; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC ATPases; EC Reticulum Calcium-Transporting ATPases

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