Lysophosphatidic acid inhibits Ca2+ signaling in response to epidermal growth factor receptor stimulation in human astrocytoma cells by a mechanism involving phospholipase C(gamma) and a G(alphai) protein |
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Authors: | Hernández M Barrero M J Crespo M S Nieto M L |
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Institution: | Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain. |
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Abstract: | The effect of the lysophospholipid mediators lysophosphatidic acid (LPA) and sphingosine 1-phosphate and the polypeptide growth factor epidermal growth factor (EGF) on the human astrocytoma cell line 1321N1 was assessed. These agonists produced a rapid and transient increase of the intracellular Ca(2+) concentration. When LPA was perfused before addition of EGF, the EGF-dependent Ca(2+) transient was abrogated, whereas this was not observed when EGF preceded LPA addition. This inhibitory effect was not found for other EGF-mediated responses, e.g., activation of the mitogen-activated protein kinase cascade and cell proliferation, thus pointing to the existence of cross-talk between LPA and EGF for only a branch of EGF-induced responses. As 1321N1 cells expressed mRNA encoding the LPA receptors endothelial differentiation gene (Edg)-2, Edg-4, and Edg-7 and as sphingosine 1-phosphate did not interfere with LPA signaling, Edg-2, Edg-4, and/or Edg-7 could be considered as the LPA receptors mediating the aforementioned cross-talk. Attempts to address the biochemical mechanism involved in the cross-talk between the receptors were conducted by the immunoprecipitation approach using antibodies reacting with the EGF receptor (EGFR), phosphotyrosine, phospholipase Cgamma (PLCgamma)-1, and G(alphai) protein. LPA was found to induce coupling of PLCgamma-1 to the EGFR by a mechanism involving a G(alphai) protein, in the absence of tyrosine phosphorylation of both PLCgamma and the EGFR. These data show a cross-talk between LPA and EGF limited to a branch of EGFR-mediated signaling, which may be explained by a LPA-induced, G(alphai)-protein-mediated translocation of PLCgamma-1 to EGFR in the absence of detectable tyrosine phosphorylation of both proteins. |
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Keywords: | Astrocyte Growth factors Lipid mediators Mitogen-activated protein kinase Phospholipase |
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