title: Dual regulation of lysophosphatidic acid (LPA1) receptor signalling by Ral and GRK.
abstract: Lysophosphatidic acid (LPA) is a major constituent of blood and is involved in a variety of physiological and pathophysiological processes. LPA signals via the ubiquitously expressed G protein-coupled receptors (GPCRs), LPA(1) and LPA(2) that are specific for LPA. However, in large, the molecular mechanisms that regulate the signalling of these receptors are unknown. We show that the small GTPase RalA associates with both LPA(1) and LPA(2) in human embryonic kidney (HEK 293) cells and that stimulation of LPA(1) receptors with LPA triggers the activation of RalA. While RalA was not found to play a role in the endocytosis of LPA receptors, we reveal that LPA(1) receptor stimulation promoted Ral-dependent phospholipase C activity. Furthermore, we found that GRK2 is required for the desensitization of LPA(1) and LPA(2) and have identified a novel interaction between RalA and GRK2, which is promoted by LPA(1) receptor activity. Taken together, these results establish RalA and GRK2 as key regulators of LPA receptor signalling and demonstrate for the first time that LPA(1) activity facilitates the formation of a novel protein complex between these two proteins.
authors.affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Adel I
authors.initials: AI
authors.lastname: Aziziyeh
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Li
authors.forename: Cynthia
authors.initials: C
authors.lastname: Pape
authors.forename: Macarena
authors.initials: M
authors.lastname: Pampillo
authors.forename: Peter
authors.initials: P
authors.lastname: Chidiac
authors.forename: Fred
authors.initials: F
authors.lastname: Possmayer
authors.forename: Andy V
authors.initials: AV
authors.lastname: Babwah
authors.forename: Moshmi
authors.initials: M
authors.lastname: Bhattacharya
mesh_terms: D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; C483163:Ralb protein, human; D049368:Receptors, Lysophosphatidic Acid; D015544:Inositol 1,4,5-Trisphosphate; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D010738:Type C Phospholipases; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins; C032881:lysophosphatidic acid