ERBB receptor activation is required for profibrotic responses to transforming growth factor β

Mahefatiana Andrianifahanana, Mark C. Wilkes, Claire E. Repellin, Maryanne Edens, Theodore J. Kottom, Rod A. Rahimi, Edward B. Leof

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Engagement of the transforming growth factor-β (TGF-β) receptor complex activates multiple signaling pathways that play crucial roles in both health and disease. TGF-β is a key regulator of fibrogenesis and cancer-associated desmoplasia; however, its exact mode of action in these pathologic processes has remained poorly defined. Here, we report a novel mechanism whereby signaling via members of the ERBB or epidermal growth factor family of receptors serves as a central requirement for the biological responses of fibroblasts to TGF-β. We show that TGF-β triggers upregulation of ERBB ligands and activation of cognate receptors via the canonical SMAD pathway in fibroblasts. Interestingly, activation of ERBB is commonly observed in a subset of fibroblast but not epithelial cells from different species, indicating cell type specificity. Moreover, using genetic and pharmacologic approaches, we show that ERBB activation by TGF-β is essential for the induction of fibroblast cell morphologic transformation and anchorage-independent growth. Together, these results uncover important aspects of TGF-β signaling that highlight the role of ERBB ligands/receptors as critical mediators in fibroblast responses to this pleiotropic cytokine.

Original languageEnglish (US)
Pages (from-to)7421-7430
Number of pages10
JournalCancer research
Volume70
Issue number19
DOIs
StatePublished - Oct 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Andrianifahanana, M., Wilkes, M. C., Repellin, C. E., Edens, M., Kottom, T. J., Rahimi, R. A., & Leof, E. B. (2010). ERBB receptor activation is required for profibrotic responses to transforming growth factor β. Cancer research, 70(19), 7421-7430. https://doi.org/10.1158/0008-5472.CAN-10-0232