HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 28, 19501-19511, July 14, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/28/19501    most recent M511224200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhao, Y. Articles by Natarajan, V. Search for Related Content PubMed PubMed Citation Articles by Zhao, Y. Articles by Natarajan, V. Social Bookmarking                      What's this?

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^*

Yutong Zhao, Donghong He, Bahman Saatian, Tonya Watkins, Ernst Wm. Spannhake^¶, Nigel J. Pyne^||, and Viswanathan Natarajan¹

From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, ^¶Department of Environmental Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, and ^||Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow GN 0NR, Scotland, United Kingdom

We have demonstrated earlier that lysophosphatidic acid (LPA)-induced interleukin-8 (IL-8) secretion is regulated by protein kinase C (PKC)-dependent NF-B 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 PKC or pretreatment with a PKC 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 PKC 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 PKC-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.

Received for publication, October 14, 2005 , and in revised form, May 4, 2006.

^* This work was supported in part by National Institutes of Health Grant HL71152 (to V. N.) and from the Biotechnology and Biological Sciences Research Council, Swindon, United Kingdom (to N. J. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Section of Pulmonary and Critical Care, Dept. of Medicine, University of Chicago, Center for Integrative Science Bldg., Rm. 408B, 929 East 57th St., Chicago, IL 60637. Tel.: 773-834-2638; Fax: 773-834-2687; E-mail: vnataraj{at}medicine.bsd.uchicago.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Xing, Z. Zhang, H. Mao, R. G. Schnellmann, and S. Zhuang Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms Am J Physiol Renal Physiol, July 1, 2008; 295(1): F145 - F152. [Abstract] [Full Text] [PDF]

				K. M. Kassel, P. R. Dodmane, N. A. Schulte, and M. L. Toews Lysophosphatidic Acid Induces Rapid and Sustained Decreases in Epidermal Growth Factor Receptor Binding via Different Signaling Pathways in BEAS-2B Airway Epithelial Cells J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 809 - 817. [Abstract] [Full Text] [PDF]

				C. L. Quement, I. Guenon, J.-Y. Gillon, V. Lagente, and E. Boichot MMP-12 induces IL-8/CXCL8 secretion through EGFR and ERK1/2 activation in epithelial cells Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1076 - L1084. [Abstract] [Full Text] [PDF]

				S. Zhuang, G. R. Kinsey, K. Rasbach, and R. G. Schnellmann Heparin-binding epidermal growth factor and Src family kinases in proliferation of renal epithelial cells Am J Physiol Renal Physiol, March 1, 2008; 294(3): F459 - F468. [Abstract] [Full Text] [PDF]

				J. Q. van der Merwe, M. D. Hollenberg, and W. K. MacNaughton EGF receptor transactivation and MAP kinase mediate proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, February 1, 2008; 294(2): G441 - G451. [Abstract] [Full Text] [PDF]

				K. M. Kassel, N. A. Schulte, S. M. Parker, A. D. Lanik, and M. L. Toews Lysophosphatidic Acid Decreases Epidermal Growth Factor Receptor Binding in Airway Epithelial Cells J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 109 - 118. [Abstract] [Full Text] [PDF]

				F. Wang, C. Sloss, X. Zhang, S. W. Lee, and J. C. Cusack Membrane-Bound Heparin-Binding Epidermal Growth Factor Like Growth Factor Regulates E-Cadherin Expression in Pancreatic Carcinoma Cells Cancer Res., September 15, 2007; 67(18): 8486 - 8493. [Abstract] [Full Text] [PDF]

				M. Seo, M.-J. Lee, J. H. Heo, Y.-I. Lee, Y. Kim, S.-Y. Kim, E.-S. Lee, and Y.-S. Juhnn G Protein beta{gamma} Subunits Augment UVB-induced Apoptosis by Stimulating the Release of Soluble Heparin-binding Epidermal Growth Factor from Human Keratinocytes J. Biol. Chem., August 24, 2007; 282(34): 24720 - 24730. [Abstract] [Full Text] [PDF]

				J. Huang, J. Hu, X. Bian, K. Chen, W. Gong, N. M. Dunlop, O.M. Z. Howard, and J. M. Wang Transactivation of the Epidermal Growth Factor Receptor by Formylpeptide Receptor Exacerbates the Malignant Behavior of Human Glioblastoma Cells Cancer Res., June 15, 2007; 67(12): 5906 - 5913. [Abstract] [Full Text] [PDF]

				H. Zhang, A. Bialkowska, R. Rusovici, S. Chanchevalap, H. Shim, J. P. Katz, V. W. Yang, and C. C. Yun Lysophosphatidic Acid Facilitates Proliferation of Colon Cancer Cells via Induction of Kruppel-like Factor 5 J. Biol. Chem., May 25, 2007; 282(21): 15541 - 15549. [Abstract] [Full Text] [PDF]

				H.-J. Im, P. Muddasani, V. Natarajan, T. M. Schmid, J. A. Block, F. Davis, A. J. van Wijnen, and R. F. Loeser Basic Fibroblast Growth Factor Stimulates Matrix Metalloproteinase-13 via the Molecular Cross-talk between the Mitogen-activated Protein Kinases and Protein Kinase C{delta} Pathways in Human Adult Articular Chondrocytes J. Biol. Chem., April 13, 2007; 282(15): 11110 - 11121. [Abstract] [Full Text] [PDF]

				Y. Zhao, D. He, J. Zhao, L. Wang, A. R. Leff, E. Wm. Spannhake, S. Georas, and V. Natarajan Lysophosphatidic Acid Induces Interleukin-13 (IL-13) Receptor {alpha}2 Expression and Inhibits IL-13 Signaling in Primary Human Bronchial Epithelial Cells J. Biol. Chem., April 6, 2007; 282(14): 10172 - 10179. [Abstract] [Full Text] [PDF]

				T. T. Chiu, W. Y. Leung, M. P. Moyer, R. M. Strieter, and E. Rozengurt Protein kinase D2 mediates lysophosphatidic acid-induced interleukin 8 production in nontransformed human colonic epithelial cells through NF-{kappa}B Am J Physiol Cell Physiol, February 1, 2007; 292(2): C767 - C777. [Abstract] [Full Text] [PDF]

				A. C. Snider and K. E. Meier Receptor transactivation cascades. Focus on "Effects of {alpha}1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells" Am J Physiol Cell Physiol, January 1, 2007; 292(1): C1 - C3. [Full Text] [PDF]