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Research ArticleCELLULAR AND MOLECULAR

Lysophosphatidic Acid Induces Rapid and Sustained Decreases in Epidermal Growth Factor Receptor Binding via Different Signaling Pathways in BEAS-2B Airway Epithelial Cells

Karen M. Kassel, Puttappa R. Dodmane, Nancy A. Schulte and Myron L. Toews
Journal of Pharmacology and Experimental Therapeutics June 2008, 325 (3) 809-817; DOI: https://doi.org/10.1124/jpet.107.133736
Karen M. Kassel
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Puttappa R. Dodmane
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Nancy A. Schulte
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Myron L. Toews
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Abstract

Lysophosphatidic acid (LPA) and epidermal growth factor (EGF) are important mediators of lung cell function and lung diseases. We showed previously that LPA decreases epidermal growth factor receptor (EGFR) binding rapidly in BEAS-2B airway epithelial cells, and this decrease is sustained to at least 18 h. The current studies investigate which LPA signaling pathways mediate the rapid versus sustained decreases in EGFR binding in BEAS-2B cells. The Gi/o inhibitor pertussis toxin and the Rho kinase inhibitor Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide] had no effect on the rapid or sustained decreases. However, the mitogen-activated protein kinase kinase (MEK) inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)-butadiene ethanolate] decreased extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, completely inhibited the rapid decrease in binding, and partially inhibited the sustained decrease. The direct Ca2+- and phospholipid-dependent protein kinase (PKC) activator phorbol-12-myristate-13-acetate stimulated ERK1/2 phosphorylation and decreased EGFR binding at both 15 min and 18 h. Furthermore, inhibitors of PKC partially inhibited ERK1/2 phosphorylation and the 15-min decrease but completely inhibited the 18-h decrease. Inhibitor time course studies showed that PKC induction of the 18-h decrease occurred during the first 3 h of treatment. We showed previously that LPA-stimulated EGFR transactivation contributes to the rapid decrease. Two transactivation inhibitors partially inhibited ERK1/2 phosphorylation, and U0126 partially inhibited EGFR transactivation, indicating that MEK may be involved both upstream and downstream of EGFR activation. Together, the data presented here indicate that LPA mediates the rapid decrease in EGFR binding via EGFR transactivation, MEK/ERK, and PKC, whereas the sustained decrease is regulated primarily by PKC.

Footnotes

  • This study was supported by American Heart Fellowship 0415367Z and a Skala Fellowship (to K.M.K.) and by GlaxoSmithKline Grant 100909 and Nebraska Department of Health and Human Services Grant 2007-39 (to M.L.T.).

  • Portions of this work were published as part of a dissertation: Kassel KM (2007) Regulation of epidermal growth factor receptors and mitogenic signaling by lysophosphatidic acid and β2 adrenergic receptors in airway cells. Ph.D. thesis, University of Nebraska Medical Center, Omaha, NE.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.133736.

  • ABBREVIATIONS: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; LPA, lysophosphatidic acid; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; PKC, Ca2+- and phospholipid-dependent protein kinase; HASM, human airway smooth muscle; RO 31-8220, 2-[1-(3-(amidinothio)propyl)-1H-indol-3-yl]-3-(1-methylindol-3-yl) maleimide · methanesulfonate; GM6001, N-[(2R)-2-hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide; Y-27632, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide; Bisindolylmaleimide I, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide; AG1478, 4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline; PMA, phorbol-12-myristate-13-acetate; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene ethanolate; DN, dominant negative; DMEM, Dulbecco's modified Eagle's medium; BSA, bovine serum albumin; PBS, phosphate-buffered saline; PTx, pertussis toxin; Bis I, Bisinolylmaleimide I; MMP, matrix metalloproteinase; PAGE, polyacrylamide gel electrophoresis; COPD, chronic obstructive pulmonary disease.

    • Received October 29, 2007.
    • Accepted February 27, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleCELLULAR AND MOLECULAR

Lysophosphatidic Acid Induces Rapid and Sustained Decreases in Epidermal Growth Factor Receptor Binding via Different Signaling Pathways in BEAS-2B Airway Epithelial Cells

Karen M. Kassel, Puttappa R. Dodmane, Nancy A. Schulte and Myron L. Toews
Journal of Pharmacology and Experimental Therapeutics June 1, 2008, 325 (3) 809-817; DOI: https://doi.org/10.1124/jpet.107.133736

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Research ArticleCELLULAR AND MOLECULAR

Lysophosphatidic Acid Induces Rapid and Sustained Decreases in Epidermal Growth Factor Receptor Binding via Different Signaling Pathways in BEAS-2B Airway Epithelial Cells

Karen M. Kassel, Puttappa R. Dodmane, Nancy A. Schulte and Myron L. Toews
Journal of Pharmacology and Experimental Therapeutics June 1, 2008, 325 (3) 809-817; DOI: https://doi.org/10.1124/jpet.107.133736
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