title: The sphingosine 1-phosphate receptor S1P4 regulates cell shape and motility via coupling to Gi and G12/13.
abstract: Sphingosine 1-phosphate (S1P) receptors represent a novel subfamily of G-protein-coupled receptors binding S1P specifically and with high affinity. Although their in vivo functions remain largely unknown, in vitro extracellular application of S1P induces distinct S1P receptor-dependent cellular responses including proliferation, differentiation, and migration. We have analyzed signaling pathways engaged by S1P(4), which is highly expressed in the lymphoid system. Here we show that S1P(4) couples directly to Galpha(i) and even more effectively to Galpha(12/13)-subunits of trimeric G-proteins, but not to Galpha(q) unlike other S1P receptors. Consequently, CHO-K1 cells ectopically expressing S1P(4) potently activate the small GTPase Rho and undergo cytoskeletal rearrangements, inducing peripheral stress fiber formation and cell rounding, upon S1P stimulation. Overexpression of S1P(4) in Jurkat T cells induces pertussis toxin-sensitive cell motility even in the absence of exogenously added S1P. In addition, S1P(4) is internalized upon binding of S1P. The capacity of S1P(4) to mediate cellular responses, such as motility and shape change through Galpha(i)- and Galpha(12/13)-coupled signaling pathways may be important for its in vivo function which is currently under investigation.
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Centrum of Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Gräler
authors.forename: Robert
authors.initials: R
authors.lastname: Grosse
authors.forename: Angelika
authors.initials: A
authors.lastname: Kusch
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000502:physiology*; D048429:Cell Size / Q000502:physiology*; D006224:Cricetinae; D004789:Enzyme Activation; D005453:Fluorescence; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins