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 RxRxxpST. 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.
%0 Journal Article
%1 frickePhosphoproteomicsProfilingDefines2023a
%A Fricke, Anna L.
%A Mühlhäuser, Wignand W. D.
%A Reimann, Lena
%A Zimmermann, Johannes P.
%A Reichenbach, Christa
%A Knapp, Bettina
%A Peikert, Christian D.
%A Heberle, Alexander M.
%A Faessler, Erik
%A Schäuble, Sascha
%A Hahn, Udo
%A Thedieck, Kathrin
%A Radziwill, Gerald
%A Warscheid, Bettina
%C United States
%D 2023
%J Journal of proteome research
%K (KSEA),kinasesubstrate (PRM),Phosphorylation,protein *Phosphatidylinositol 3-Kinases/metabolism,*Proto-Oncogene 70-kDa,Ribosomal 90-kDa,RXRXXS/T Fibers Kinases Protein Proteins S6 Skeletal/metabolism,parallel Transduction/physiology,skeletal acids amino analysis by c-akt/genetics/metabolism,cross cell cells,stable culture,text enrichment in inhibitors,kinasesubstrate isotope labeling mining,to_read monitoring motif,signal muscle phosphorylation,quantification,Ribosomal reaction relationship,label-free,mass spectrometry,Muscle talk,kinase transduction,Signal
%N 3
%P 768--789
%R 10.1021/acs.jproteome.2c00505
%T Phosphoproteomics Profiling Defines a Target Landscape of the Basophilic Protein Kinases AKT, S6K, and RSK in Skeletal Myotubes.
%V 22
%X 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 RxRxxpST. 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.
@article{frickePhosphoproteomicsProfilingDefines2023a,
abstract = {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.},
added-at = {2024-05-17T13:01:35.000+0200},
address = {United States},
author = {Fricke, Anna L. and M{\"u}hlh{\"a}user, Wignand W. D. and Reimann, Lena and Zimmermann, Johannes P. and Reichenbach, Christa and Knapp, Bettina and Peikert, Christian D. and Heberle, Alexander M. and Faessler, Erik and Sch{\"a}uble, Sascha and Hahn, Udo and Thedieck, Kathrin and Radziwill, Gerald and Warscheid, Bettina},
biburl = {https://www.bibsonomy.org/bibtex/24f6daaf407078b0cd2e258d3acbb8a6a/warscheidlab},
doi = {10.1021/acs.jproteome.2c00505},
interhash = {7376a79dcd5771086c342079e7a1cb7a},
intrahash = {4f6daaf407078b0cd2e258d3acbb8a6a},
issn = {1535-3907 1535-3893},
journal = {Journal of proteome research},
keywords = {(KSEA),kinasesubstrate (PRM),Phosphorylation,protein *Phosphatidylinositol 3-Kinases/metabolism,*Proto-Oncogene 70-kDa,Ribosomal 90-kDa,RXRXXS/T Fibers Kinases Protein Proteins S6 Skeletal/metabolism,parallel Transduction/physiology,skeletal acids amino analysis by c-akt/genetics/metabolism,cross cell cells,stable culture,text enrichment in inhibitors,kinasesubstrate isotope labeling mining,to_read monitoring motif,signal muscle phosphorylation,quantification,Ribosomal reaction relationship,label-free,mass spectrometry,Muscle talk,kinase transduction,Signal},
langid = {english},
month = mar,
number = 3,
pages = {768--789},
pmid = {36763541},
timestamp = {2024-05-17T13:01:35.000+0200},
title = {Phosphoproteomics {{Profiling Defines}} a {{Target Landscape}} of the {{Basophilic Protein Kinases AKT}}, {{S6K}}, and {{RSK}} in {{Skeletal Myotubes}}.},
volume = 22,
year = 2023
}