title: Notch and TGF-β pathways cooperatively regulate receptor protein tyrosine phosphatase-κ (PTPRK) gene expression in human primary keratinocytes.
abstract: Receptor protein tyrosine phosphatase-κ (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-β/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-β pathways in regulation of PTPRK expression in human keratinocytes. Suppression of Notch signaling by γ-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-β1 and TGF-β receptor inhibitor SB431542 inhibited contact-induced expression of PTPRK. Furthermore, inhibition of Notch signaling, via knockdown of Notch1 or by γ-secretase inhibitors, significantly reduced TGF-β-induced PTPRK gene expression, indicating that Notch and TGF-β pathways function together to regulate PTPRK. Of importance, the combination of Jag1 plus TGF-β results in greater PTPRK expression and lower EGFR tyrosine phosphorylation than either ligand alone. These data indicate that Notch and TGF-β act in concert to stimulate induction of PTPRK, which suppresses EGFR activation in human keratinocytes.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109 xuyiru@umich.edu.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Siliang
authors.initials: S
authors.lastname: Xue
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D002450:Cell Communication; D002478:Cells, Cultured; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology*; D061251:Primary Cell Culture; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; C512478:EGFR protein, human; D066246:ErbB Receptors; C489852:PTPRK protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2