title: FGF1-mediated cardiomyocyte cell cycle reentry depends on the interaction of FGFR-1 and Fn14.
abstract: Fibroblast growth factors (FGFs) signal through FGF receptors (FGFRs) mediating a broad range of cellular functions during embryonic development, as well as disease and regeneration during adulthood. Thus, it is important to understand the underlying molecular mechanisms that modulate this system. Here, we show that FGFR-1 can interact with the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) resulting in cardiomyocyte cell cycle reentry. FGF1-induced cell cycle reentry in neonatal cardiomyocytes could be blocked by Fn14 inhibition, while TWEAK-induced cell cycle activation was inhibited by blocking FGFR-1 signaling. In addition, costimulation experiments revealed a synergistic effect of FGF1 and TWEAK in regard to cardiomyocyte cell cycle induction via PI3K/Akt signaling. Overexpression of Fn14 with either FGFR-1 long [FGFR-1(L)] or FGFR-1 short [FGFR-1(S)] isoforms resulted after FGF1/TWEAK stimulation in cell cycle reentry of >40% adult cardiomyocytes. Finally, coimmunoprecipitation and proximity ligation assays indicated that endogenous FGFR-1 and Fn14 interact with each other in cardiomyocytes. This interaction was strongly enhanced in the presence of their corresponding ligands, FGF1 and TWEAK. Taken together, our data suggest that FGFR-1/Fn14 interaction may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control cardiomyocyte cell cycle reentry.
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; felix.engel@uk-erlangen.de tatyana.novoyatleva@innnere.med.uni-giessen.de.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Novoyatleva
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Government College University Faisalabad, Faisalabad, Pakistan;
authors.forename: Amna
authors.initials: A
authors.lastname: Sajjad
authors.affiliation: Membrane Transport Machineries Group, Cluster of Excellence Frankfurt-Macromolecular Complexes, Institute of Biochemistry, Goethe University of Frankfurt, Frankfurt am Main, Germany;
authors.forename: Denys
authors.initials: D
authors.lastname: Pogoryelov
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Chinmoy
authors.initials: C
authors.lastname: Patra
authors.affiliation: Department of Pulmonary Pharmacotherapy, Justus Liebig University Giessen, Giessen, Germany; and.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany felix.engel@uk-erlangen.de tatyana.novoyatleva@innnere.med.uni-giessen.de.
authors.forename: Felix B
authors.initials: FB
authors.lastname: Engel
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D000074049:Cytokine TWEAK; D016220:Fibroblast Growth Factor 1 / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000074049:Cytokine TWEAK; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613300:Tnfrsf12a protein, rat; C497771:Tnfsf12 protein, rat; D048069:Tumor Necrosis Factors; C112971:fibroblast growth factor 14; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: TWEAK; heart; signaling