Thromboxane A2 receptor-mediated epidermal growth factor receptor transactivation: Involvement of PKC-δ and PKC-ε in the shedding of epidermal growth factor receptor ligands

Kotomi Uchiyama, Masaki Saito, Masako Sasaki, Yutaro Obara, Shigeki Higashiyama, Norimichi Nakahata

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

We examined thromboxane A2 receptor (TP)-mediated transactivation of epidermal growth factor receptor (EGFR) through the shedding of EGFR ligands. A TP agonist U46619 caused the phosphorylation of EGFR in 1321N1 human astrocytoma cells, which was inhibited by an EGFR selective inhibitor AG1478 and by a disintegrin and metalloproteinase (ADAM) inhibitor TAPI-2, indicating TP stimulation caused the EGFR transactivation through the EGFR ligand shedding. Since 1321N1 cells expressed heparin-binding EGF (HB-EGF) mRNA, the mechanism of TP-mediated EGFR transactivation was examined in HEK293 cells expressing alkaline phosphatase-conjugated HB-EGF and TP. U46619 caused the shedding of HB-EGF in a time- and concentration-dependent manner. The TP-mediated shedding was inhibited by a furin inhibitor CMK, TAP-2, dominant-negative Gαq, a Gq/11 inhibitor YM254890, and also by a non-selective PKC inhibitor GF109203X and PKC down-regulation, but not by a conventional PKC inhibitor Gö6976. Furthermore, siRNAs of PKC-δ and PKC-ε inhibited U46619-induced HB-EGF shedding. Although BAPTA/AM had no effect on U46619-induced shedding of HB-EGF, EGTA inhibited it. These results suggest that TP-mediated EGFR transactivation is partially caused by shedding of HB-EGF, which involves furin and ADAM via novel types of PKCs (PKC-δ and PKC-ε) through Gαq/11 proteins in an extracellular Ca2+-dependent manner.

Original languageEnglish
Pages (from-to)504-511
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume38
Issue number5
DOIs
Publication statusPublished - 2009 Dec 8

Keywords

  • Epidermal growth factor receptor
  • G protein
  • Heparin-binding epidermal growth factor
  • Protein kinase C
  • Thromboxane A receptor
  • Transactivation

ASJC Scopus subject areas

  • Pharmaceutical Science

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