Ligand release-independent transactivation of epidermal growth factor receptor by transforming growth factor-β involves multiple signaling pathways

Abstract

Many of the signaling responses induced by transforming growth factor-b (TGF-b) are mediated by Smad proteins, but there is evidence that it can also signal independently of Smads. Here, we provide evidence that multiple signal pathways induced by TGF-b1-including Src family tyrosine kinases (SFKs), generation of reactive oxygen species (ROS), de novo protein synthesis and E-cadherindependent cell-cell interactions-transactivate the epidermal growth factor receptor (EGFR), which in turn regulates expression of c-Fos and c-Jun. Immunoprecipitation and immunofluorescence staining showed that EGFR was phosphorylated on tyrosine in response to TGF-b1. EGFR transactivation required the activation of SFKs and the production of ROS via NADPH oxidase, but was not dependent on metalloproteases or the release of EGF-like ligands. In addition, the production of ROS was dependent on signaling by specific SFKs as well as de novo protein synthesis. Stable transfection of E-cadherin into MDA-MB-231 cells as well as E-cadherin-blocking assays revealed that E-cadherin-mediated cell-cell interactions were also essential for EGFR transactivation. Finally, EGFR transactivation was involved in the expression of c-Fos and c-Jun via the extracellular signal-regulated kinase signaling cascade. Taken together our data suggest that ligand release-independent transactivation of EGFR may diversify early TGF-b signaling and represent a novel pathway leading to TGF-b-mediated gene expression.

EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

“…Previous studies suggested that Src kinase may directly activate TGFb and that TGFb-mediated ROS production can also induce EGFRdependent Src kinase activation. [27][28][29] We propose that such a vicious cycle may exist: Ang II-ROS-Src-EGFR signaling induces TGFb activation, which may in turn, further increase ROS production and Src kinase activity, thereby further enhancing TGFbdependent fibrogenesis. This study also suggests a potential therapeutic intervention to target progressive renal injury.…”

Inhibition of E-Cadherin Dependent Cell-Cell Contact Promotes MUC5AC Mucin Production through the Activation of Epidermal Growth Factor Receptors

“…14) However, ligand release-independent transactivation of EGFR is also recognized. 15) Thus multiple mechanisms are responsible for the transactivation of EGFR. 10,14) We have found that anti-Ecadherin antibody stimulated ERK1/2 phosphorylation, and that MUC5AC production, which was promoted by the anti-E-cadherin antibody, was inhibited by an EGFR inhibitor in NCI-H292 cells.…”

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

“…Transactivation of the EGF receptor (EGFR) by TGF-␤ 1 can also stimulate PI3 kinase and Akt (22,36,37,52). This has been linked to Smad-induced increases in the synthesis of the EGF receptor ligands (36), such as heparin-binding EGF, stimulation of c-Src-family kinases (22,37), induction of NADPH oxidase (36,37), PKC (52), and activation of TNF-␣-converting enzyme (TACE), which leads to the shedding of EGFR ligands (37).…”