Overexpression of c-Met and CD44v6 receptors contributes to autocrine TGF-β1 signaling in interstitial lung disease

J Biol Chem. 2014 Mar 14;289(11):7856-72. doi: 10.1074/jbc.M113.505065. Epub 2013 Dec 9.


The hepatocyte growth factor (HGF) and the HGF receptor Met pathway are important in the pathogenesis of interstitial lung disease (ILD). Alternatively spliced isoforms of CD44 containing variable exon 6 (CD44v6) and its ligand hyaluronan (HA) alter cellular function in response to interaction between CD44v6 and HGF. TGF-β1 is the crucial cytokine that induces fibrotic action in ILD fibroblasts (ILDFbs). We have identified an autocrine TGF-β1 signaling that up-regulates both Met and CD44v6 mRNA and protein expression. Western blot analysis, flow cytometry, and immunostaining revealed that CD44v6 and Met colocalize in fibroblasts and in tissue sections from ILD patients and in lungs of bleomycin-treated mice. Interestingly, cell proliferation induced by TGF-β1 is mediated through Met and CD44v6. Further, cell proliferation mediated by TGF-β1/CD44v6 is ERK-dependent. In contrast, action of Met on ILDFb proliferation does not require ERK but does require p38(MAPK). ILDFbs were sorted into CD44v6(+)/Met(+) and CD44v6(-)/Met(+) subpopulations. HGF inhibited TGF-β1-stimulated collagen-1 and α-smooth muscle cell actin expression in both of these subpopulations by interfering with TGF-β1 signaling. HGF alone markedly stimulated CD44v6 expression, which in turn regulated collagen-1 synthesis. Our data with primary lung fibroblast cultures with respect to collagen-1, CD44v6, and Met expressions were supported by immunostaining of lung sections from bleomycin-treated mice and from ILD patients. These results define the relationships between CD44v6, Met, and autocrine TGF-β1 signaling and the potential modulating influence of HGF on TGF-β1-induced CD44v6-dependent fibroblast function in ILD fibrosis.

Keywords: Cd44; Collagen; Fibroblast; Pulmonary Fibrosis; Transforming Growth Factor beta (TGFbeta).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Culture Media / chemistry
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Gene Expression Regulation
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Lung / pathology
  • Lung Diseases, Interstitial / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-met / metabolism*
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction*
  • Transforming Growth Factor beta1 / metabolism*


  • CD44v6 antigen
  • Culture Media
  • Hyaluronan Receptors
  • RNA, Messenger
  • Transforming Growth Factor beta1
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met