title: 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.
abstract: 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 betagamma subunits) or beta-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.
authors: Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor St., Glasgow G4 ONR, UK.
authors: Noreen Akhtar
authors: NA
authors: Moughal
authors: Catherine
authors: C
authors: Waters
authors: Balwinder
authors: B
authors: Sambi
authors: Susan
authors: S
authors: Pyne
authors: Nigel J
authors: NJ
authors: Pyne
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D008246:Lysophospholipids; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011993:Recombinant Fusion Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C032881:lysophosphatidic acid