title: Galpha(q)-mediated plasma membrane translocation of sphingosine kinase-1 and cross-activation of S1P receptors.
abstract: Sphingosine-1-phosphate (S1P), formed by sphingosine kinases (SphKs), regulates cellular proliferation and migration by acting as an agonist at specific receptors or intracellularly. Since S1P's effects are probably dependent on subcellular localization of its formation and degradation, we have studied the influence of G protein-coupled receptors on the localization of SphK1. Activation of Gq-coupled receptors induced a profound, rapid (half-life 3-5 s) and long-lasting (> 2 h) translocation of SphK1 to the plasma membrane. This was mimicked by expression of constitutively active G protein alpha-subunits specifically of the Gq family. Classical Gq signalling pathways, or phosphorylation at Ser225, phospholipase D and Ca2+/calmodulin were not involved in M3 receptor-induced SphK1 translocation in HEK-293 cells. Translocation was associated with S1P receptor internalization, which was dependent on catalytic activity of SphK1 and S1P receptor binding and thus resulted from S1P receptor cross-activation. It is concluded that SphK1 is an important effector of Gq-coupled receptors, linking them via cross-activation of S1P receptors to G(i) and G12/13 signalling pathways.
authors.affiliation: Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: ter Braak
authors.forename: Kerstin
authors.initials: K
authors.lastname: Danneberg
authors.forename: Karin
authors.initials: K
authors.lastname: Lichte
authors.forename: Kerstin
authors.initials: K
authors.lastname: Liphardt
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Ktistakis
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.forename: Karl H
authors.initials: KH
authors.lastname: Jakobs
authors.forename: Dagmar
authors.initials: D
authors.lastname: Meyer zu Heringdorf
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D004075:Diglycerides / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010739:Phospholipase D / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D004075:Diglycerides; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D010739:Phospholipase D; D010768:Phosphoserine; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D043587:Receptor, Muscarinic M3; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C061800:N,N-dimethylsphingosine