Transforming Growth Factor-β Signaling Strength Determines Target Gene Expression Profile in Human Keratinocytes

ABSTRACT

Transforming Growth Factor-β (TGFβ) maintains keratinocyte homeostasis, and induces epithelial-tomesenchymal transition (EMT) in response to tissue injury. To investigate how these two TGFβ responses might become uncoupled during malignant transformation, we examined the TGFβ-regulated gene expression programs and cellular responses in human keratinocytes as a function of TGFβ type I receptor (TβR-I) kinase activity and TGFβ level. The TGFβ- mediated homeostatic gene response program and cellular growth arrest were extremely sensitive to a reduction in receptor kinase activity, while much stronger inhibition of TGFβ receptor activity was needed to inhibit the tissue injury response gene expression program and EMT. Both endogenous TGFβ and high exogenous levels of TGFβ induced the homeostatic response, while only high levels of TGFβ induced EMT. These results suggest that a reduction in receptor signaling activity may be sufficient for keratinocytes to escape from TGFβ’s tumor suppressor function, while higher levels of TGFβ associated with tumor progression are pro-invasive/metastatic. These findings have important implications for the optimal use of TGFβ/Smad signaling antagonists as anti-cancer therapeutics.