Imperial College London
Alternate

ProfessorDavidCarling

Faculty of Medicine, Institute of Clinical Sciences

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)7590 250 559david.carling

 
 
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Location

 

2.14DLMS BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Thomas:2018:10.1042/BCJ20180475,
author = {Thomas, EC and Hook, SC and Gray, A and Chadt, A and Carling, D and Al-Hasani, H and Heesom, KJ and Hardie, DG and Tavare, JM},
doi = {10.1042/BCJ20180475},
journal = {Biochemical Journal},
pages = {2969--2983},
title = {Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity},
url = {http://dx.doi.org/10.1042/BCJ20180475},
volume = {475},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energyhomeostasis which achieves this through the phosphorylation of a myriad of downstreamtargets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucoseuptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which maybe important in regulating glucose uptake. Here, we show AMPK heterotrimers containingthe α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosinebinding (PTB) domains of TBC1D1 and is increased by two different pharmacologicalactivators of AMPK (AICAR and A769962). The interaction enhances the efficiency bywhich AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237. Furthermore, theinteraction is reduced by a naturally occurring R125W mutation in the PTB1 domain ofTBC1D1, previously found to be associated with severe familial obesity in females, with aconcomitant reduction in Ser237 phosphorylation. Our observations provide evidence fora functional difference between AMPK α-subunits and extend the repertoire of proteinkinases that interact with substrates via stabilisation mechanisms that modify the efficacyof substrate phosphorylation.
AU  - Thomas,EC
AU  - Hook,SC
AU  - Gray,A
AU  - Chadt,A
AU  - Carling,D
AU  - Al-Hasani,H
AU  - Heesom,KJ
AU  - Hardie,DG
AU  - Tavare,JM
DO  - 10.1042/BCJ20180475
EP  - 2983
PY  - 2018///
SN  - 1470-8728
SP  - 2969
TI  - Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity
T2  - Biochemical Journal
UR  - http://dx.doi.org/10.1042/BCJ20180475
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000445512100006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/69517
VL  - 475
ER  -
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