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Papers In Press, published online ahead of print May 10, 2006
Medicine/Pulmonary & Critical Care, The University of Chicago, Chicago, IL 60637
Corresponding Author: vnataraj{at}medicine.bsd.uchicago.edu
We have demonstrated earlier that LPA-induced interleukin-8 (IL-8) secretion is regulated by PKC d dependent NF-B activation in human bronchial epithelial cells (HBEpCs) [Cummings et. al., (2004) J. Biol. Chem. 278, 41085-41094]. Here we provide evidence for signaling pathways that regulate LPA-mediated transactivation of epidermal growth factor receptor (EGF-R) and the role of cross-talk between G-protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) in IL-8 secretion in HBEpCs. Treatment of HBEpCs with LPA stimulated tyrosine phosphorylation of EGF-R at tyrosine residues 845, 992, 1068 and 1173, which was attenuated by matrix metalloproteinase (MMP) inhibitor (GM6001), HB-EGF inhibitor (CRM 197), and HB-EGF neutralizing antibody. Over expression of dominant negative PKC d or pretreatment with a PKC d inhibitor (rottlerin) or Src kinase family inhibitor (PP2) partially blocked LPA-induced MMP activation, proHB-EGF shedding and EGF-R tyrosine phosphorylation. Down regulation of Lyn kinase, but not Src kinase, by specific siRNA mitigated LPA-induced MMP activation, proHB-EGF shedding and EGF-R phosphorylation. In addition, over expression of dominant negative PKC d blocked LPA-induced phosphorylation and translocation of Lyn kinase to the plasma membrane. Furthermore, down regulation of EGF-R by EGF-R siRNA or pretreatment of cells with EGF-R inhibitors, AG1478 & PD158780, almost completely blocked LPA-dependent EGF-R phosphorylation and partially attenuated IL-8 secretion, respectively. These results demonstrate that LPA-induced IL-8 secretion is partly dependent on EGF-R transactivation regulated by PKC d -dependent activation of Lyn kinase and MMPs, and proHB-EGF shedding suggesting a novel mechanism of cross talk and interaction between GPCRs and RTKs in HBEpCs.
J. Biol. Chem, 10.1074/jbc.M511224200
Submitted on October 14, 2005
Revised on May 4, 2006
Accepted on May 10, 2006
Regulation of lysophosphatidic acid- induced epidermal growth factor receptor transactivation and interleukin-8 secretion in human bronchial epithelial cells by protein kinase C
, Lyn kinase and matrix metalloproteinases
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