Protein tyrosine phosphatase α mediates profibrotic signaling in lung fibroblasts through TGF-β responsiveness

Am J Pathol. 2014 May;184(5):1489-502. doi: 10.1016/j.ajpath.2014.01.016. Epub 2014 Mar 17.


Fibrotic lung diseases represent a diverse group of progressive and often fatal disorders with limited treatment options. Although the pathogenesis of these conditions remains incompletely understood, receptor type protein tyrosine phosphatase α (PTP-α encoded by PTPRA) has emerged as a key regulator of fibroblast signaling. We previously reported that PTP-α regulates cellular responses to cytokines and growth factors through integrin-mediated signaling and that PTP-α promotes fibroblast expression of matrix metalloproteinase 3, a matrix-degrading proteinase linked to pulmonary fibrosis. Here, we sought to determine more directly the role of PTP-α in pulmonary fibrosis. Mice genetically deficient in PTP-α (Ptpra(-/-)) were protected from pulmonary fibrosis induced by intratracheal bleomycin, with minimal alterations in the early inflammatory response or production of TGF-β. Ptpra(-/-) mice were also protected from pulmonary fibrosis induced by adenoviral-mediated expression of active TGF-β1. In reciprocal bone marrow chimera experiments, the protective phenotype tracked with lung parenchymal cells but not bone marrow-derived cells. Because fibroblasts are key contributors to tissue fibrosis, we compared profibrotic responses in wild-type and Ptpra(-/-) mouse embryonic and lung fibroblasts. Ptpra(-/-) fibroblasts exhibited hyporesponsiveness to TGF-β, manifested by diminished expression of αSMA, EDA-fibronectin, collagen 1A, and CTGF. Ptpra(-/-) fibroblasts exhibited markedly attenuated TGF-β-induced Smad2/3 transcriptional activity. We conclude that PTP-α promotes profibrotic signaling pathways in fibroblasts through control of cellular responsiveness to TGF-β.

Publication types

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

MeSH terms

  • Adenoviridae
  • Animals
  • Bleomycin
  • Cytokines / biosynthesis
  • Fibroblasts / pathology*
  • Gene Deletion
  • Genes, Reporter
  • Lung / pathology*
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Pneumonia / complications
  • Pneumonia / pathology
  • Pulmonary Fibrosis / complications
  • Pulmonary Fibrosis / pathology*
  • Pulmonary Fibrosis / prevention & control
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / deficiency
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / metabolism*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Smad Proteins / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / metabolism*


  • Cytokines
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta
  • Bleomycin
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4