PtdIns(3,4,5)P3 is an established second messenger of growth-factor and insulin-induced signalling pathways. There is increasing evidence that one of the immediate breakdown products of PtdIns(3,4,5)P3, namely PtdIns(3,4)P2, whose levels are elevated by numerous extracellular agonists, might also function as a signalling molecule. Recently, we identified two related pleckstrin-homology (PH)-domain-containing proteins, termed ‘tandem-PH-domain-containing protein-1’ (TAPP1) and TAPP2, which interacted in vitro with high affinity with PtdIns(3,4)P2, but did not bind PtdIns(3,4,5)P3 or other phosphoinositides. In the present study we demonstrate that stimulation of Swiss 3T3 or 293 cells with agonists that stimulate PtdIns(3,4)P2 production results in the marked translocation of TAPP1 to the plasma membrane. This recruitment is dependent on a functional PtdIns(3,4)P2-binding PH domain and is inhibited by wortmannin, a phosphoinositide 3-kinase inhibitor that prevents PtdIns(3,4)P2 generation. A search for proteins that interact with TAPP1 identified the multi-PDZ-containing protein termed ‘MUPP1’, a protein possessing 13 PDZ domains and no other known modular or catalytic domains [PDZ is postsynaptic density protein (PSD-95)/Drosophila disc large tumour suppressor (dlg)/tight junction protein (ZO1)]. We demonstrate that immunoprecipitation of endogenously expressed TAPP1 from 293-cell lysates results in the co-immunoprecipitation of endogenous MUPP1, indicating that these proteins are likely to interact with each other physiologically. We show that TAPP1 and TAPP2 interact with the 10th and 13th PDZ domain of MUPP1 through their C-terminal amino acids. The results of the present study suggest that TAPP1 and TAPP2 could function in cells as adapter proteins to recruit MUPP1, or other proteins that they may interact with, to the plasma membrane in response to signals that elevate PtdIns(3,4)P2.
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February 2002
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Research Article|
January 25 2002
Evidence that the tandem-pleckstrin-homology-domain-containing protein TAPP1 interacts with Ptd(3,4)P2 and the multi-PDZ-domain-containing protein MUPP1 in vivo
Wendy A. KIMBER;
Wendy A. KIMBER
1
∗MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
1To whom correspondence should be addressed (e-mail w.a.kimber@dundee.ac.uk).
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Laura TRINKLE-MULCAHY;
Laura TRINKLE-MULCAHY
‡School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Peter C. F. CHEUNG;
Peter C. F. CHEUNG
∗MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Maria DEAK;
Maria DEAK
∗MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Louisa J. MARSDEN;
Louisa J. MARSDEN
∗MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Agnieszka KIELOCH;
Agnieszka KIELOCH
†Division of Signal Transduction Therapy, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Stephen WATT;
Stephen WATT
‡School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Ronald T. JAVIER;
Ronald T. JAVIER
§Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
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Alex GRAY;
Alex GRAY
†Division of Signal Transduction Therapy, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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C. Peter DOWNES;
C. Peter DOWNES
†Division of Signal Transduction Therapy, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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John M. LUCOCQ;
John M. LUCOCQ
‡School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Dario R. ALESSI
Dario R. ALESSI
∗MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Publisher: Portland Press Ltd
Received:
September 17 2001
Revision Received:
November 07 2001
Accepted:
November 27 2001
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 361 (3): 525–536.
Article history
Received:
September 17 2001
Revision Received:
November 07 2001
Accepted:
November 27 2001
Citation
Wendy A. KIMBER, Laura TRINKLE-MULCAHY, Peter C. F. CHEUNG, Maria DEAK, Louisa J. MARSDEN, Agnieszka KIELOCH, Stephen WATT, Ronald T. JAVIER, Alex GRAY, C. Peter DOWNES, John M. LUCOCQ, Dario R. ALESSI; Evidence that the tandem-pleckstrin-homology-domain-containing protein TAPP1 interacts with Ptd(3,4)P2 and the multi-PDZ-domain-containing protein MUPP1 in vivo. Biochem J 1 February 2002; 361 (3): 525–536. doi: https://doi.org/10.1042/bj3610525
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