title: Fibulin-6 regulates pro-fibrotic TGF-β responses in neonatal mouse ventricular cardiac fibroblasts.
abstract: Fibulin-6, an essential component of extracellular matrix determines the architecture of cellular junctions in tissues undergoing strain. Increased expression and deposition of fibulin-6 facilitates fibroblast migration in response to TGF-β, following myocardial infarction in mouse heart. The underlying mechanism still remains elusive. In conjunction with our previous study, we have now demonstrated that in fibulin-6 knockdown (KD) fibroblasts, not only TGF-β dependent migration, but also stress fiber formation, cellular networking and subsequently fibroblast wound contraction is almost abrogated. SMAD dependent TGF-β pathway shows ~75% decreased translocation of R-SMAD and co-SMAD into the nucleus upon fibulin-6 KD. Consequently, SMAD dependent pro-fibrotic gene expression is considerably down regulated to basal levels both in mRNA and protein. Also, investigating the non-SMAD pathways we observed a constitutive increase in pERK-levels in fibulin-6 KD fibroblast compared to control, but no change was seen in pAKT. Immunoprecipitation studies revealed 60% reduced interaction of TGF-β receptor II and I (TGFRII and I) accompanied by diminished phosphorylation of TGFRI at serin165 in fibulin-6 KD cells. In conclusion, fibulin-6 plays an important role in regulating TGF-β mediated responses, by modulating TGF-β receptor dimerization and activation to further trigger downstream pathways.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.|Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Arpita
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hasselbach
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Echtermeyer
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jyotsana
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.|Perioperative Inflammation and Infection, Department of Human Medicine, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Herzog
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D016326:Extracellular Matrix Proteins; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C517185:hemicentin 1 protein, mouse