title: Common pathways regulate Type III TGFβ receptor-dependent cell invasion in epicardial and endocardial cells.
abstract: Epithelial-Mesenchymal Transformation (EMT) and the subsequent invasion of epicardial and endocardial cells during cardiac development is critical to the development of the coronary vessels and heart valves. The transformed cells give rise to cardiac fibroblasts and vascular smooth muscle cells or valvular interstitial cells, respectively. The Type III Transforming Growth Factor β (TGFβR3) receptor regulates EMT and cell invasion in both cell types, but the signaling mechanisms downstream of TGFβR3 are not well understood. Here we use epicardial and endocardial cells in in vitro cell invasion assays to identify common mechanisms downstream of TGFβR3 that regulate cell invasion. Inhibition of NF-κB activity blocked cell invasion in epicardial and endocardial cells. NF-κB signaling was found to be dysregulated in Tgfbr3(-/-) epicardial cells which also show impaired cell invasion in response to ligand. TGFβR3-dependent cell invasion is also dependent upon Activin Receptor-Like Kinase (ALK) 2, ALK3, and ALK5 activity. A TGFβR3 mutant that contains a threonine to alanine substitution at residue 841 (TGFβR3-T841A) induces ligand-independent cell invasion in both epicardial and endocardial cells in vitro. These findings reveal a role for NF-κB signaling in the regulation of epicardial and endocardial cell invasion and identify a mutation in TGFβR3 which stimulates ligand-independent signaling.
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: cynthia.r.allison@vanderbilt.edu.
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Clark
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: jamille.robinson@vanderbilt.edu.
authors.forename: Jamille Y
authors.initials: JY
authors.lastname: Robinson
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: NSSanchez@mdanderson.org.
authors.forename: Nora S
authors.initials: NS
authors.lastname: Sanchez
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: ttownsend@genetics.utah.edu.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Townsend
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: julian.a.arrieta@Vanderbilt.edu.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Arrieta
authors.affiliation: Dept. of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212. Electronic address: david.merryman@vanderbilt.edu.
authors.forename: W David
authors.initials: WD
authors.lastname: Merryman
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: david.trykall@vanderbilt.edu.
authors.forename: David Z
authors.initials: DZ
authors.lastname: Trykall
authors.affiliation: Dept. of Biology, Indiana University-Northwest, Gary, IN 46408, United States. Electronic address: holivey@iun.edu.
authors.forename: Harold E
authors.initials: HE
authors.lastname: Olivey
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, United States; Research Medicine, Veterans Affairs TVHS, Nashville, TN 37212, United States. Electronic address: charles.c.hong@vanderbilt.edu.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: joey.barnett@vanderbilt.edu.
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
mesh_terms: D029404:Activin Receptors / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D004699:Endocardium / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010496:Pericardium / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D018125:Receptors, Transforming Growth Factor beta; D029404:Activin Receptors
keywords: Bone morphogenic protein; Endocardial cell; Epicardial cell; Invasion; Nuclear factor-kappa B; Transforming Growth Factor Beta