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

ABSTRACT: Engagement of the transforming growth factor-? (TGF-?) receptor complex activates multiple signaling pathways that play crucial roles in both health and disease. TGF-? 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-?. We show that TGF-? 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-? is essential for the induction of fibroblast cell morphologic transformation and anchorage-independent growth. Together, these results uncover important aspects of TGF-? signaling that highlight the role of ERBB ligands/receptors as critical mediators in fibroblast responses to this pleiotropic cytokine.

SUBMITTER: Andrianifahanana M 

PROVIDER: S-EPMC3093933 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature