Ligand release-independent transactivation of epidermal growth factor receptor by transforming growth factor-beta involves multiple signaling pathways.
Many of the signaling responses induced by transforming growth factor-beta (TGF-beta) 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-beta1-including Src family tyrosine kinases (SFKs), generation of reactive oxygen species (ROS), de novo protein synthesis and E-cadherin-dependent 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-beta1. 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-beta signaling and represent a novel pathway leading to TGF-beta-mediated gene expression.
Joo
C-K
CK
Laboratory of Visual Science, Korea Eye Tissue and Gene Bank, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Kim
H-S
HS
Park
J-Y
JY
Seomun
Y
Y
Son
M-J
MJ
Kim
J-T
JT
D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes; D008024:Ligands; D014176:Protein Biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D015820:Cadherins; D008024:Ligands; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors; D019061:src-Family Kinases