Phosphoproteomics Profiling Defines a Target Landscape of the Basophilic Protein Kinases AKT, S6K, and RSK in Skeletal Myotubes

Anna L. Fricke, Wignand W.D. Mühlhäuser, Lena Reimann, Johannes P. Zimmermann, Christa Reichenbach, Bettina Knapp, Christian D. Peikert, Alexander M. Heberle, Erik Faessler, Sascha Schäuble, Udo Hahn, Kathrin Thedieck, Gerald Radziwill, Bettina Warscheid*

*Bijbehorende auteur voor dit werk

    OnderzoeksoutputAcademicpeer review


    Phosphorylation-dependent signal transduction plays an important role in regulating the functions and fate of skeletal muscle cells. Central players in the phospho-signaling network are the protein kinases AKT, S6K, and RSK as part of the PI3K-AKT-mTOR-S6K and RAF-MEK-ERK-RSK pathways. However, despite their functional importance, knowledge about their specific targets is incomplete because these kinases share the same basophilic substrate motif RxRxxp[ST]. To address this, we performed a multifaceted quantitative phosphoproteomics study of skeletal myotubes following kinase inhibition. Our data corroborate a cross talk between AKT and RAF, a negative feedback loop of RSK on ERK, and a putative connection between RSK and PI3K signaling. Altogether, we report a kinase target landscape containing 49 so far unknown target sites. AKT, S6K, and RSK phosphorylate numerous proteins involved in muscle development, integrity, and functions, and signaling converges on factors that are central for the skeletal muscle cytoskeleton. Whereas AKT controls insulin signaling and impinges on GTPase signaling, nuclear signaling is characteristic for RSK. Our data further support a role of RSK in glucose metabolism. Shared targets have functions in RNA maturation, stability, and translation, which suggests that these basophilic kinases establish an intricate signaling network to orchestrate and regulate processes involved in translation.

    Originele taal-2English
    Pagina's (van-tot)768-789
    Aantal pagina's22
    TijdschriftJournal of Proteome Research
    Nummer van het tijdschrift3
    Vroegere onlinedatumfeb.-2023
    StatusPublished - 3-mrt.-2023

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