Regulation of lysophosphatidic acid-induced epidermal growth factor receptor transactivation and interleukin-8 secretion in human bronchial epithelial cells by protein kinase Cδ, lyn kinase, and matrix metalloproteinases

Yutong Zhao, Donghong He, Bahman Saatian, Tonya Watkins, Ernst Wm Spannhake, Nigel J. Pyne, Viswanathan Natarajan

Research output: Contribution to journalArticle

Abstract

We have demonstrated earlier that lysophosphatidic acid (LPA)-induced interleukin-8 (IL-8) secretion is regulated by protein kinase Cδ (PKCδ)-dependent NF-κB activation in human bronchial epithelial cells (HBEpCs). Here we provide evidence for signaling pathways that regulate LPA-mediated transactivation of epidermal growth factor receptor (EGFR) and the role of cross-talk between G-protein-coupled receptors and receptor-tyrosine kinases in IL-8 secretion in HBEpCs. Treatment of HBEpCs with LPA stimulated tyrosine phosphorylation of EGFR, which was attenuated by matrix metalloproteinase (MMP) inhibitor (GM6001), heparin binding (HB)-EGF inhibitor (CRM 197), and HB-EGF neutralizing antibody. Overexpression of dominant negative PKCδ or pretreatment with a PKCδ inhibitor (rottlerin) or Src kinase family inhibitor (PP2) partially blocked LPA-induced MMP activation, proHB-EGF shedding, and EGFR tyrosine phosphorylation. Down-regulation of Lyn kinase, but not Src kinase, by specific small interfering RNA mitigated LPA-induced MMP activation, proHB-EGF shedding, and EGFR phosphorylation. In addition, overexpression of dominant negative PKCδ blocked LPA-induced phosphorylation and translocation of Lyn kinase to the plasma membrane. Furthermore, down-regulation of EGFR by EGFR small interfering RNA or pretreatment of cells with EGFR inhibitors AG1478 and PD158780 almost completely blocked LPA-dependent EGFR phosphorylation and partially attenuated IL-8 secretion, respectively. These results demonstrate that LPA-induced IL-8 secretion is partly dependent on EGFR transactivation regulated by PKCδ-dependent activation of Lyn kinase and MMPs and proHB-EGF shedding, suggesting a novel mechanism of crosstalk and interaction between G-protein-coupled receptors and receptor-tyrosine kinases in HBEpCs.

Original languageEnglish (US)
Pages (from-to)19501-19511
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number28
DOIs
StatePublished - Jul 14 2006

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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