Notch and TGF-beta pathways cooperatively regulate receptor protein tyrosine phosphatase-kappa (PTPRK) gene expression in human primary keratinocytes

作者：Xu Yiru^*; Xue Siliang; Zhou Jin; Voorhees John J; Fisher Gary J

来源：Molecular Biology of the Cell, 2015, 26(6): 1199-1206.

DOI：10.1091/mbc.E14-12-1591

Receptor protein tyrosine phosphatase-kappa (PTPRK) specifically and directly dephosphorylates epidermal growth factor receptor (EGFR), thereby limiting EGFR function in primary human keratinocytes. PTPRK expression is increased by the TGF-beta/Smad3 pathway and cell-cell contact. Because the Notch receptor pathway is responsive to cell-cell contact and regulates keratinocyte growth and differentiation, we investigated the interplay between Notch and TGF-beta pathways in regulation of PTPRK expression in human keratinocytes. Suppression of Notch signaling by gamma-secretase inhibitors substantially reduced cell contact induction of PTPRK gene expression. In sparse keratinocyte cultures, addition of soluble Notch-activating ligand jagged one peptide (Jag1) induced PTPRK. Of interest, cell contact-induced expression of TGF-beta 1 and TGF-beta receptor inhibitor SB431542 inhibited contact-induced expression of PTPRK. Furthermore, inhibition of Notch signaling, via knockdown of Notch1 or by gamma-secretase inhibitors, significantly reduced TGF-beta-induced PTPRK gene expression, indicating that Notch and TGF-beta pathways function together to regulate PTPRK. Of importance, the combination of Jag1 plus TGF-beta results in greater PTPRK expression and lower EGFR tyrosine phosphorylation than either ligand alone. These data indicate that Notch and TGF-beta act in concert to stimulate induction of PTPRK, which suppresses EGFR activation in human keratinocytes.

• 出版日期2015-3-15