Cub domain-containing protein 1 negatively regulates TGF-beta signaling and myofibroblast differentiation

Noskovicova, Nina; Heinzelmann, Katharina; Burgstaller, Gerald; Behr, Jürgen und Eickelberg, Oliver (2018): Cub domain-containing protein 1 negatively regulates TGF-beta signaling and myofibroblast differentiation. In: American Journal of Physiology-Lung Cellular and Molecular Physiology, Bd. 314, Nr. 5: L695-L707

Abstract

Fibroblasts are thought to be the prime cell type for producing and secreting extracellular matrix (ECM) proteins in the connective tissue. The profibrotic cytokine transforming growth factor-beta 1 (TGF-beta 1) activates and transdifferentiates fibroblasts into alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblasts, which exhibit increased ECM secretion, in particular collagens. Little information, however, exists about cell-surface molecules on fibroblasts that mediate this transdifferentiation process. We recently identified, using unbiased cellsurface proteome analysis, Cub domain-containing protein 1 (CDCP1) to be strongly downregulated by TGF-beta 1. CDCP1 is a transmembrane glycoprotein, the expression and role of which has not been investigated in lung fibroblasts to date. Here, we characterized, in detail, the effect of TGF-beta 1 on CDCP1 expression and function, using immunofluorescence, FACS, immunoblotting, and siRNA-mediated knockdown of CDCP1. CDCP1 is present on interstitial fibroblasts, but not myofibroblasts, in the normal and idiopathic pulmonary fibrosis lung. In vitro, TGF-beta 1 decreased CDCP1 expression in a time-dependent manner by impacting mRNA and protein levels. Knockdown of CDCP1 enhanced a TGF-beta 1-mediated cell adhesion of fibroblasts. Importantly, CDCP1-depleted cells displayed an enhanced expression of profibrotic markers, such as collagen V or alpha-SMA, which was found to be independent of TGF-beta 1. Our data show, for the very first time that loss of CDCP1 contributes to fibroblast to myofibroblast differentiation via a potential negative feedback loop between CDCP1 expression and TGF-beta 1 stimulation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1040-0605
• Sprache: Englisch