Insulin sensitivity is critically dependent on the activity of PI3K (phosphoinositide 3-kinase) and generation of the PtdIns(3,4,5)P3 second messenger. PtdIns(3,4,5)P3 can be broken down to PtdIns(3,4)P2 through the action of the SHIPs (Src-homology-2-domain-containing inositol phosphatases). As PtdIns(3,4)P2 levels peak after those of PtdIns(3,4,5)P3, it has been proposed that PtdIns(3,4)P2 controls a negative-feedback loop that down-regulates the insulin and PI3K network. Previously, we identified two related adaptor proteins termed TAPP [tandem PH (pleckstrin homology)-domain-containing protein] 1 and TAPP2 that specifically bind to PtdIns(3,4)P2 through their C-terminal PH domain. To determine whether TAPP1 and TAPP2 play a role in regulating insulin sensitivity, we generated knock-in mice that express normal endogenous levels of mutant TAPP1 and TAPP2 that are incapable of binding PtdIns(3,4)P2. These homozygous TAPP1R211L/R211LTAPP2R218L/R218L double knock-in mice are viable and exhibit significantly enhanced activation of Akt, a key downstream mediator of insulin signalling. Consistent with increased PI3K and Akt activity, the double knock-in mice display enhanced whole body insulin sensitivity and disposal of glucose uptake into muscle tissues. We also generated wild-type and double TAPP1R211L/R211LTAPP2R218L/R218L knock-in embryonic fibroblasts and found that insulin triggered enhanced production of PtdIns(3,4,5)P3 and Akt activity in the double knock-in fibroblasts. These observations provide the first genetic evidence to support the notion that binding of TAPP1 and TAPP2 adap-tors to PtdIns(3,4)P2 function as negative regulators of the insulin and PI3K signalling pathways.
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Research Article|
February 11 2011
Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4)P2 in regulating insulin sensitivity defined by knock-in analysis
Stephan Wullschleger;
Stephan Wullschleger
1
*MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
1Correspondence may be addressed to either of these authors (email s.wullschleger@dundee.ac.uk or d.r.alessi@dundee.ac.uk).
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David H. Wasserman;
David H. Wasserman
†Vanderbilt-NIH Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
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Alex Gray;
Alex Gray
‡Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Kei Sakamoto;
Kei Sakamoto
*MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
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Dario R. Alessi
Dario R. Alessi
1
*MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
1Correspondence may be addressed to either of these authors (email s.wullschleger@dundee.ac.uk or d.r.alessi@dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
December 01 2010
Revision Received:
December 22 2010
Accepted:
January 04 2011
Accepted Manuscript online:
January 04 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 434 (2): 265–274.
Article history
Received:
December 01 2010
Revision Received:
December 22 2010
Accepted:
January 04 2011
Accepted Manuscript online:
January 04 2011
Citation
Stephan Wullschleger, David H. Wasserman, Alex Gray, Kei Sakamoto, Dario R. Alessi; Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4)P2 in regulating insulin sensitivity defined by knock-in analysis. Biochem J 1 March 2011; 434 (2): 265–274. doi: https://doi.org/10.1042/BJ20102012
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