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

Zhao, Y. and He, D. and Saatian, B. and Watkins, T. and Spannhake, E.W. and Pyne, N.J. and Natarajan, V. (2006) Regulation of lysophosphatidic acid-induced epidermal growth factor receptor transactivation and interleukin-8 secretion in human bronchial epithelial cells by protein kinase cdelta, lyn kinase, and matrix metalloproteinases. Journal of Biological Chemistry, 281 (28). pp. 19501-19511. ISSN 0021-9258

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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 cross-talk and interaction between G-protein-coupled receptors and receptor-tyrosine kinases in HBEpCs.

Item type: Article
ID code: 10413
Keywords: lysophosphatidic acid , heparin binding, epidermal growth factor, human bronchial epithelial cells, matrix metalloproteinase, platelet-derived growth factor receptor, mitogenactivated protein kinase, bronchial epithelial basal medium, phosphatidic acid, enzyme-linked immunosorbent assay, multiplicity of infection, Pharmacy and materia medica, Biochemistry, Cell Biology, Molecular Biology
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
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Depositing user: Strathprints Administrator
Date Deposited: 02 Dec 2011 11:37
Last modified: 01 Oct 2014 12:37
URI: http://strathprints.strath.ac.uk/id/eprint/10413

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