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Disruption of fyn SH3 domain interaction with a proline-rich motif in liver kinase B1 results in activation of AMP-activated protein kinase
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Yamada, Eijiro and Bastie, Claire C. (2014) Disruption of fyn SH3 domain interaction with a proline-rich motif in liver kinase B1 results in activation of AMP-activated protein kinase. PLoS ONE , Volume 9 (Number 2). Article number e89604. doi:10.1371/journal.pone.0089604 ISSN 1932-6203.
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Official URL: http://dx.doi.org/10.1371/journal.pone.0089604
Abstract
Fyn-deficient mice display increased AMP-activated Protein Kinase (AMPK) activity as a result of Fyn-dependent regulation of Liver Kinase B1 (LKB1) in skeletal muscle. Mutation of Fyn-specific tyrosine sites in LKB1 results in LKB1 export into the cytoplasm and increased AMPK activation site phosphorylation. This study characterizes the structural elements responsible for the physical interaction between Fyn and LKB1. Effects of point mutations in the Fyn SH2/SH3 domains and in the LKB1 proline-rich motif on 1) Fyn and LKB1 binding, 2) LKB1 subcellular localization and 3) AMPK phosphorylation were investigated in C2C12 muscle cells. Additionally, novel LKB1 proline-rich motif mimicking cell permeable peptides were generated to disrupt Fyn/LKB1 binding and investigate the consequences on AMPK activity in both C2C12 cells and mouse skeletal muscle. Mutation of either Fyn SH3 domain or the proline-rich motif of LKB1 resulted in the disruption of Fyn/LKB1 binding, re-localization of 70% of LKB1 signal in the cytoplasm and a 2-fold increase in AMPK phosphorylation. In vivo disruption of the Fyn/LKB1 interaction using LKB1 proline-rich motif mimicking cell permeable peptides recapitulated Fyn pharmacological inhibition. We have pinpointed the structural elements within Fyn and LKB1 that are responsible for their binding, demonstrating the functionality of this interaction in regulating AMPK activity.
| Item Type: | Journal Article | ||||||
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| Subjects: | Q Science > QP Physiology | ||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Protein kinases, Mice -- Physiology | ||||||
| Journal or Publication Title: | PLoS ONE | ||||||
| Publisher: | Public Library of Science | ||||||
| ISSN: | 1932-6203 | ||||||
| Official Date: | 25 February 2014 | ||||||
| Dates: |
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| Volume: | Volume 9 | ||||||
| Number: | Number 2 | ||||||
| Article Number: | Article number e89604 | ||||||
| DOI: | 10.1371/journal.pone.0089604 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||
| Date of first compliant deposit: | 26 December 2015 | ||||||
| Date of first compliant Open Access: | 26 December 2015 | ||||||
| Funder: | National Institutes of Health (U.S.) (NIH) | ||||||
| Grant number: | DK81412 (NIH) |
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