Common Pathways Regulate Type Iii Tgf Beta Receptor-Dependent Cell Invasion In Epicardial And Endocardial Cells

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 beta (TGF beta R3) receptor regulates EMT and cell invasion in both cell types, but the signaling mechanisms downstream of TGF beta R3 are not well understood. Here we use epicardial and endocardial cells in in vitro cell invasion assays to identify common mechanisms downstream of TGF beta R3 that regulate cell invasion. Inhibition of NF-kappa B activity blocked cell invasion in epicardial and endocardial cells. NF-kappa B signaling was found to be dysregulated in tGFBR3(-/-) epicardial cells which also show impaired cell invasion in response to ligand. TGF beta R3-dependent cell invasion is also dependent upon Activin Receptor-Like Kinase (ALK) 2, ALK3, and ALK5 activity. A TGF beta R3 mutant that contains a threonine to alanine substitution at residue 841 (TGF beta R3-T841A) induces ligand-independent cell invasion in both epicardial and endocardial cells in vitro. These findings reveal a role for NF-kappa B signaling in the regulation of epicardial and endocardial cell invasion and identify a mutation in TGF beta R3 which stimulates ligand-independent signaling. (C) 2016 Elsevier Inc All rights reserved.