Nerve growth factor signaling involves interaction between the Trk A receptor and lysophosphatidate receptor 1 systems: nuclear translocation of the lysophosphatidate receptor 1 and Trk A receptors in pheochromocytoma 12 cells

• Published in: Cellular signalling 2004, Vol.16 (1), p.127-136
• Main Authors: Moughal, Noreen Akhtar, Waters, Catherine, Sambi, Balwinder, Pyne, Susan, Pyne, Nigel J.
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Animals; Cell Nucleus - drug effects; Cell Nucleus - genetics; Cell Nucleus - metabolism; Drug Synergism; Lysophosphatidate; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Nerve growth factor; Nerve Growth Factor - metabolism; Nerve Growth Factor - pharmacology; PC12 Cells; Peptide Fragments - pharmacology; Rats; Receptor, trkA - genetics; Receptor, trkA - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Lysophosphatidic Acid; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Transfection; Trk A receptor
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2003.08.004

We report here that the nerve growth factor (NGF) and lysophosphatidate (LPA) receptor signaling systems interact to regulate the p42/p44 MAPK pathway in PC12 cells. This is based upon several lines of evidence. First, the treatment of PC12 cells, which express LPA 1 receptors, with a sub-maximal concentration of LPA and NGF induced synergistic activation of p42/p44 MAPK. Second, the transfection of PC12 cells with LPA 1 receptor anti-sense construct, which reduced the expression of LPA 1, abrogated both LPA- and NGF-stimulated activation of p42/p44 MAPK. Third, the over-expression of recombinant LPA 1 receptor potentiated LPA- and NGF-dependent activation of p42/p44 MAPK. Fourth, the over-expression of C-terminal GRK2 peptide (which sequesters G-protein βγ subunits) or β-arrestin I clathrin binding domain (amino acids: 319–418) or pre-treatment of cells with pertussis toxin reduced the LPA- and NGF-dependent stimulation of p42/p44 MAPK. These findings support a model in which the Trk A receptor uses a G-protein-mediated mechanism to regulate the p42/p44 MAPK pathway. Such G-protein-mediated signaling is activated by the LPA 1 receptor as a means of cross-talk regulation with the Trk A receptor. Fifth, the treatment of cells with LPA induced the transactivation of the Trk A receptor. Sixth, LPA and/or NGF stimulated the translocation of tyrosine phosphorylated Trk A receptor and LPA 1 receptor to the nucleus. Taken together, these findings suggest that NGF and LPA exert cross-talk regulation both at the level of p42/p44 MAPK signaling and in the nuclear translocation of LPA 1 and Trk A receptors.