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Cell Signal. 2016 Jun;28(6):688-98. doi: 10.1016/j.cellsig.2016.03.004. Epub 2016 Mar 10.

Common pathways regulate Type III TGFβ receptor-dependent cell invasion in epicardial and endocardial cells.

Author information

1
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: cynthia.r.allison@vanderbilt.edu.
2
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: jamille.robinson@vanderbilt.edu.
3
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: NSSanchez@mdanderson.org.
4
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: ttownsend@genetics.utah.edu.
5
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: julian.a.arrieta@Vanderbilt.edu.
6
Dept. of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212. Electronic address: david.merryman@vanderbilt.edu.
7
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: david.trykall@vanderbilt.edu.
8
Dept. of Biology, Indiana University-Northwest, Gary, IN 46408, United States. Electronic address: holivey@iun.edu.
9
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.
10
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.

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.

KEYWORDS:

Bone morphogenic protein; Endocardial cell; Epicardial cell; Invasion; Nuclear factor-kappa B; Transforming Growth Factor Beta

PMID:
26970186
PMCID:
PMC4827451
DOI:
10.1016/j.cellsig.2016.03.004
[Indexed for MEDLINE]
Free PMC Article

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