Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress
Abstract The actin-binding protein filamin c (FLNc) is a key mediator in the response of skeletal muscle cells to mechanical stress. In addition to its function as a structural scaffold, FLNc acts as a signaling adaptor which is phosphorylated at S2234 in its mechanosensitive domain 20 (d20) through...
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Nature Portfolio
2024-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-78953-8 |
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| author | Thomas Kokot Johannes P. Zimmermann Anja N. Schwäble Lena Reimann Anna L. Herr Nico Höfflin Maja Köhn Bettina Warscheid |
| author_facet | Thomas Kokot Johannes P. Zimmermann Anja N. Schwäble Lena Reimann Anna L. Herr Nico Höfflin Maja Köhn Bettina Warscheid |
| author_sort | Thomas Kokot |
| collection | DOAJ |
| description | Abstract The actin-binding protein filamin c (FLNc) is a key mediator in the response of skeletal muscle cells to mechanical stress. In addition to its function as a structural scaffold, FLNc acts as a signaling adaptor which is phosphorylated at S2234 in its mechanosensitive domain 20 (d20) through AKT. Here, we discovered a strong dephosphorylation of FLNc-pS2234 in cultured skeletal myotubes under acute mechanical stress, despite high AKT activity. We found that all three protein phosphatase 1 (PP1) isoforms are part of the FLNc d18-21 interactome. Enzymatic assays demonstrate that PP1 efficiently dephosphorylates FLNc-pS2234 and in vitro and in cells upon PP1 activation using specific modulators. FLNc-pS2234 dephosphorylation promotes the interaction with FILIP1, a mediator for filamin degradation. Altogether, we present a model in which dephosphorylation of FLNc d20 by the dominant action of PP1c prevails over AKT activity to promote the binding of the filamin degradation-inducing factor FILIP1 during acute mechanical stress. |
| format | Article |
| id | doaj-art-e1e6dae86a4345cd82820886d087b40c |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-e1e6dae86a4345cd82820886d087b40c2025-08-20T02:13:55ZengNature PortfolioScientific Reports2045-23222024-11-0114111810.1038/s41598-024-78953-8Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stressThomas Kokot0Johannes P. Zimmermann1Anja N. Schwäble2Lena Reimann3Anna L. Herr4Nico Höfflin5Maja Köhn6Bettina Warscheid7Integrative Signaling Research, Institute of Biology III, University of FreiburgBiochemistry II, Theodor-Boveri-Institut, Biozentrum, Faculty of Chemistry and Pharmacy, University of WürzburgBiochemistry - Functional Proteomics, Institute of Biology II, University of FreiburgBiochemistry - Functional Proteomics, Institute of Biology II, University of FreiburgBiochemistry - Functional Proteomics, Institute of Biology II, University of FreiburgIntegrative Signaling Research, Institute of Biology III, University of FreiburgIntegrative Signaling Research, Institute of Biology III, University of FreiburgBiochemistry II, Theodor-Boveri-Institut, Biozentrum, Faculty of Chemistry and Pharmacy, University of WürzburgAbstract The actin-binding protein filamin c (FLNc) is a key mediator in the response of skeletal muscle cells to mechanical stress. In addition to its function as a structural scaffold, FLNc acts as a signaling adaptor which is phosphorylated at S2234 in its mechanosensitive domain 20 (d20) through AKT. Here, we discovered a strong dephosphorylation of FLNc-pS2234 in cultured skeletal myotubes under acute mechanical stress, despite high AKT activity. We found that all three protein phosphatase 1 (PP1) isoforms are part of the FLNc d18-21 interactome. Enzymatic assays demonstrate that PP1 efficiently dephosphorylates FLNc-pS2234 and in vitro and in cells upon PP1 activation using specific modulators. FLNc-pS2234 dephosphorylation promotes the interaction with FILIP1, a mediator for filamin degradation. Altogether, we present a model in which dephosphorylation of FLNc d20 by the dominant action of PP1c prevails over AKT activity to promote the binding of the filamin degradation-inducing factor FILIP1 during acute mechanical stress.https://doi.org/10.1038/s41598-024-78953-8 |
| spellingShingle | Thomas Kokot Johannes P. Zimmermann Anja N. Schwäble Lena Reimann Anna L. Herr Nico Höfflin Maja Köhn Bettina Warscheid Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress Scientific Reports |
| title | Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress |
| title_full | Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress |
| title_fullStr | Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress |
| title_full_unstemmed | Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress |
| title_short | Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress |
| title_sort | protein phosphatase 1 regulates the binding of filamin c to filip1 in cultured skeletal muscle cells under mechanical stress |
| url | https://doi.org/10.1038/s41598-024-78953-8 |
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