Receptor Type Protein Tyrosine Phosphatase-Kappa Mediates Cross-Talk between Transforming Growth Factor-Beta and Epidermal Growth Factor Receptor Signaling Pathways in Human Keratinocytes

摘要

Epidermal growth factor receptor (EGFR) signaling pathways promote human keratinocyte survival and proliferation. In contrast, transforming growth factor-beta (TGF-β) signaling pathways are strongly anti-proliferative. Receptor type protein tyrosine phosphatase-kappa (RPTP-κ) specifically dephosphorylates EGFR, thereby blocking EGFR-dependent signaling, and inhibiting proliferation. We report here that RPTP-κ mediates functional integration of EGFR and TGF-β signaling pathways in human keratinocytes. TGF-β up-regulates RPTP-κ mRNA and protein, in a dose and time dependent manner. Induction of RPTP-κ by TGF-β significantly decreases basal and EGF-stimulated EGFR tyrosine phosphorylation. shRNA-mediated reduction of TGF-β–induced RPTP-κ significantly attenuates the ability of TGF-β to inhibit proliferation. RPTP-κ induction is dependent on activation of transcription factors Smad3 and Smad4. Inhibition of TGF-β receptor kinase completely prevents induction of RPTP-κ. Chromatin immunoprecipitation assays reveal that TGF-β stimulates Smad3 and Smad4 binding to RPTP-κ gene promoter. Smad3/4 binding is localized to an 186-base pair region, which contains a consensus Smad3-binding element. These data describe a novel mechanism of cross-talk between EGFR and TGF-β pathways, in which RPTP-κ functions to integrate growth-promoting and growth-inhibiting signaling pathways.