Sphingosine Kinase Type 2 Activation by ERK-mediated Phosphorylation

Sphingosine 1-phosphate (S1P), a potent lipid mediator, is a ligand for a family of five G protein-coupled receptors (S1P1–5) that have been shown to regulate a variety of biological responses important for cancer progression. The cellular level of S1P is low and tightly regulated in a spatio-tempor...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-04, Vol.282 (16), p.12058-12065
Main Authors: Hait, Nitai C., Bellamy, Andrea, Milstien, Sheldon, Kordula, Tomasz, Spiegel, Sarah
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Cell Line, Tumor
Enzyme Activation
Epidermal Growth Factor - metabolism
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
Mitogen-Activated Protein Kinase 3 - metabolism
Molecular Sequence Data
Mutagenesis, Site-Directed
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Protein Kinase C - metabolism
Sequence Homology, Amino Acid
Threonine - chemistry
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Summary:Sphingosine 1-phosphate (S1P), a potent lipid mediator, is a ligand for a family of five G protein-coupled receptors (S1P1–5) that have been shown to regulate a variety of biological responses important for cancer progression. The cellular level of S1P is low and tightly regulated in a spatio-temporal manner through its synthesis catalyzed by two sphingosine kinases, denoted SphK1 and SphK2. Many stimuli activate and translocate SphK1 to the plasma membrane by mechanisms that are dependent on its phosphorylation. Much less is known about activation of SphK2. Here we demonstrate that epidermal growth factor (EGF) as well as the protein kinase C activator, phorbol ester, induce rapid phosphorylation of hSphK2 which was markedly reduced by inhibition of MEK1/ERK pathway. Down-regulation of ERK1 blocked EGF-induced phosphorylation of SphK2. Recombinant ERK1 phosphorylated hSphK2 in vitro and increased its enzymatic activity. ERK1 also was found to be in a complex with hSphK2 in vivo. Site-directed mutagenesis indicated that hSphK2 is phosphorylated on Ser-351 and Thr-578 by ERK1 and that phosphorylation of these residues is important for EGF-stimulated migration of MDA-MB-453 cells. These studies provide the first clues to the mechanism of agonist-mediated SphK2 activation and enhance understanding of the regulation of SphK2 activity by phosphorylation and its role in movement of human breast cancer cells toward EGF.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M609559200