Activation of sphingosine kinase by the bradykinin B2 receptor and its implication in regulation of the ERK/MAP kinase pathway.

• Sphingosine kinase phosphorylates sphingosine to generate sphingosine 1-phosphate, a phospholipid that has been implicated in signaling by a number of transmembrane receptors and was recently shown to act as a ligand for a specific class of G protein-coupled receptors. Here we show that the G protein-coupled bradykinin B2 receptor activates sphingosine kinase leading to a time- and dose-dependent elevation of cellular sphingosine 1-phosphate levels that was blocked by the sphingosine kinase inhibitor dihydrosphingosine. Furthermore, increasing doses of this inhibitor partially affected the bradykinin-mediated ERK/MAP kinase activation and fully blocked the protein kinase C-independent component of the signaling pathway from the B2 receptor to the ERK/MAP kinase cascade. Overexpression of sphingosine kinase did not additionally increase the bradykinin-induced ERK/MAP kinase activity, indicating a permissive rather than activating role of sphingosine 1-phosphate in B2 receptor-mediated mitogenic signaling.

Nyckelord

Enzyme Activation/physiology

Enzyme Inhibitors/pharmacology

Gene Expression Regulation; Enzymologic/genetics

Humans

Lysophospholipids

Mitogen-Activated Protein Kinases/biosynthesis/genetics/*metabolism

Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors/*metabolism

Receptor; Bradykinin B2

Receptors; Bradykinin/*physiology

Research Support; Non-U.S. Gov't

Signal Transduction/drug effects/physiology

Sphingosine/*analogs & derivatives/biosynthesis/pharmacology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)