ERBB receptor activation is required for profibrotic responses to transforming growth factor beta.
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.
Andrianifahanana
Mahefatiana
M
Thoracic Disease Research Unit, Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Wilkes
Mark C
MC
Repellin
Claire E
CE
Edens
Maryanne
M
Kottom
Theodore J
TJ
Rahimi
Rod A
RA
Leof
Edward B
EB
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D041701:Swiss 3T3 Cells; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
D018739:Oncogene Proteins v-erbB; D051785:Smad Proteins; D016212:Transforming Growth Factor beta