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Am J Physiol Lung Cell Mol Physiol. 2018 May 1;314(5):L695-L707. doi: 10.1152/ajplung.00205.2017. Epub 2018 Jan 4.

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

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Comprehensive Pneumology Center, University Hospital of the Ludwig-Maximilians-University Munich and Helmholtz Zentrum München, Member of the CPC-M BioArchive, Member of the German Center for Lung Research (DZL) , Munich , Germany.
Asklepios Fachkliniken München-Gauting, Munich , Germany.
Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-Maximilians-Universität, Munich , Germany.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado , Denver, Colorado.


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-β1 (TGF-β1) activates and transdifferentiates fibroblasts into α-smooth muscle actin (α-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 cell-surface proteome analysis, Cub domain-containing protein 1 (CDCP1) to be strongly downregulated by TGF-β1. 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-β1 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-β1 decreased CDCP1 expression in a time-dependent manner by impacting mRNA and protein levels. Knockdown of CDCP1 enhanced a TGF-β1-mediated cell adhesion of fibroblasts. Importantly, CDCP1-depleted cells displayed an enhanced expression of profibrotic markers, such as collagen V or α-SMA, which was found to be independent of TGF-β1. 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-β1 stimulation.


cell signaling; cell surface; fibroblast; myofibroblast differentiation; transforming growth factor-β

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