NDLI: Lysophosphatidic acid induces rapid and sustained decreases in epidermal growth factor receptor binding via different signaling pathways in BEAS-2B airway epithelial cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kassel, Karen M. Dodmane, Puttappa R. Schulte, Nancy A. Toews, Myron L.
Description	Country affiliation: United States Author Affiliation: Kassel KM ( Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5800, USA.)
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 G(i/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.
File Format	HTM / HTML
ISSN	00223565
Issue Number	3
Volume Number	325
e-ISSN	15210103
Journal	Journal of Pharmacology and Experimental Therapeutics
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2008-06-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Cell Line Research Support, Non-u.s. Gov't Signal Transduction Humans Protein-serine-threonine Kinases Epithelial Cells Pharmacology Metabolism Discipline Pharmacology Drug Effects Antagonists & Inhibitors Journal Article Lysophospholipids Discipline Therapeutics Receptor, Epidermal Growth Factor
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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