EN
RSK as a signalling scaffold to orchestrate adaptation of cardiac muscle function and metabolism (RP5)
Principial Investigators
Project Summary and Goals
The p90 ribosomal S6 kinases (RSKs) are important signaling proteins that enable cells to adapt to physiological and pathological stress conditions. Activated by ERK1/2, RSKs regulate a wide range of cellular processes, including growth, survival, metabolism, and gene expression. Dysregulation of RSK signaling has been implicated in major diseases such as heart failure and cancer, highlighting the need to better understand the mechanisms that control RSK activity and function.
Our recent work uncovered a previously unknown redox-dependent mechanism that acts as an off-switch to RSK activity. To investigate the physiological significance of this process, we developed a novel redox-dead RSK1 knock-in (KI) mouse model. Strikingly, these mice exhibit severe cardiac dysfunction, altered immune responses, impaired adaptation to chronic cardiovascular stress, and the formation of large atrial thrombi during chronic hypertensive stress conditions. These findings reveal a critical role for redox-regulated RSK signaling in maintaining cardiac function and homeostasis.
In this PhD project, we aim to determine how redox-dependent regulation of RSK1 shapes the composition and dynamics of cardiac signaling complexes and how these changes influence nuclear and mitochondrial function following myocardial infarction. The PhD candidate will work with our unique RSK1-KI mouse model and apply a broad range of cutting-edge techniques, including interactome analysis, single-cell RNA sequencing (scRNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), immunofluorescence microscopy, and advanced in vivo approaches such as experimental myocardial infarction, echocardiography and multiphoton imaging. This interdisciplinary project offers the opportunity to combine molecular, cellular, and physiological approaches to address fundamental questions in cardiac stress adaptation and disease.
Aims Addressed by the Doctoral Candidates
- Defining the role of RSK1 during myocardial ischemic injury by comparing wild-type and RSK1 knock-in mice following coronary artery ligation. This work will combine cardiac phenotyping by echocardiography with high-resolution confocal and multiphoton microscopy, as well as analysis of the composition of RSK-centered signaling complexes.
- Characterizing the cellular mechanisms underlying the RSK1 knock-in phenotype using human induced pluripotent stem cell (hiPSC)-derived cardiac cell models and advanced 3D engineered heart tissues to investigate cell type-specific functions of RSK1.
- Investigating the crosstalk between RSK and PKA signaling pathways through the analysis of RSK1 knock-in and inducible PKA-RIα conditional knockout mouse models, with a focus on understanding how these signalling networks coordinate cardiac adaptation and disease progression.
Key Techniques
- Echocardiography
- High confocal microscopy
- Intravital multiphoton microscopy
- RNA/ATAC-seq
- Generation of hiPSC lines and cardiac cell type differentiation
- Generation of 3D-Engineered Heart Tissues
- Subcellular kinase activity with FRET biosensors
Publications
-
Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development. Bedioune I, Gandon-Renard M, Dessillons M, Barthou A, Varin A, Mika D, Bichali S, Cellier J, Lechène P, Karam S, Dia M, Gomez S, Pereira de Vasconcelos W, Mercier-Nomé F, Mateo P, Dubourg A, Stratakis CA, Mercadier JJ, Benitah JP, Algalarrondo V, Leroy J, Fischmeister R, Gomez AM, Vandecasteele G (2024). Circulation. 150:2031-2045. -
PDE4 and mAKAPbeta are nodal organizers of beta2-ARs nuclear PKA signalling in cardiac myocytes. Bedioune I, Lefebvre F, Lechene P, Varin A, Domergue V, Kapiloff MS, Fishmeister R, Vandecasteele G (2018). Cardiovasc Res. 114:1499-1511. -
Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects. Tomasovic A, Brand T, Schanbacher C, Kramer S, Hümmert MW, Godoy P, Schmidt-Heck W, Nordbeck P, Ludwig J, Homann S, Wiegering A, Shaykhutdinov T, Kratz C, Knüchel R, Müller-Hermelink HK, Rosenwald A, Frey N, Eichler J, Dobrev D, El-Armouche A, Hengstler JG, Müller OJ, Hinrichs K, Cuello F, Zernecke A, Lorenz K (2020). Nat Comm. 11:1733.
-
Divergent off-target effects of RSK N-terminal and C-terminal kinase inhibitors in cardiac myocytes. Stathopoulou K, Schobesberger S, Bork NI, Sprenger JU, Perera RK, Sotoud H, Geertz B, David JP, Christ T, Nikolaev VO, Cuello F (2019). Cell Signal. 63:109362. -
Novel role for p90 ribosomal S6 kinase in the regulation of cardiac myofilament phosphorylation. Cuello F, Bardswell SC, Haworth RS, Ehler E, Sadayappan S, Kentish JC, Avkiran M (2011). J Biol Chem. 286:5300-5310. -
Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow. Orlich MM, Diéguez-Hurtado R, Muehlfriedel R, Sothilingam V, Wolburg H, Oender CE, Woelffing P, Betsholtz C, Gaengel K, Seeliger M, Adams RH, Nordheim A (2022). Circ Res. 131:308-327. -
Intravital Imaging of Disease Mechanisms in a Mouse Model of CCM Skin Lesions. Orlich MM, Norrén A, Desai MB, Holm A, Kozakewich H, Schoofs H, Mäkinen T, Bischoff J, Gaengel K (2024). Arterioscler Thromb Vasc Biol. 45:113-118.