Diacylglycerol kinase counteracts protein kinase C-mediated inactivation of the EGF receptor

J. van Baal, J. de Widt, N. Divecha, W.J. van Blitterswijk

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

Epidermal growth factor receptor (EGFR) activation is negatively regulated by protein kinase C (PKC)signaling. Stimulation of A431 cells with EGF, bradykinin or UTP increased EGFR phosphorylation at Thr654 in a PKC-dependent manner. Inhibition of PKC signaling enhanced EGFR activation, as assessed by increased phosphorylation of Tyr845 and Tyr1068 residues of the EGFR. Diacylglycerol is a physiological activator of PKC that can be removed by diacylglycerol kinase (DGK) activity. We found, in A431 and HEK293 cells, that the DGK isozyme translocated from the cytosol to the plasma membrane, where it co-localized with the EGFR and subsequently moved into EGFR-containing intracellular vesicles. This translocation was dependent on both activation of EGFR and PKC signaling. Furthermore, DGK physically interacted with the EGFR and became tyrosine-phosphorylated upon EGFR stimulation. Overexpression of DGK attenuated the bradykinin-stimulated, PKC-mediated EGFR phosphorylation at Thr654, and enhanced the phosphorylation at Tyr845 and Tyr1068. SiRNA-induced DGK downregulation enhanced this PKC-mediated Thr654 phosphorylation. Our data indicate that DGK translocation and activity is regulated by the concerted activity of EGFR and PKC and that DGK attenuates PKC-mediated Thr654 phosphorylation that is linked to desensitisation of EGFR signaling
Original languageEnglish
Pages (from-to)1791-1799
JournalInternational Journal of Biochemistry and Cell Biology
Volume44
Issue number11
DOIs
Publication statusPublished - 2012

Keywords

  • growth-factor receptor
  • signal-transduction
  • coupled receptors
  • phosphorylation
  • cells
  • src
  • transactivation
  • activation
  • mechanisms
  • expression

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