Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/27605
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Type: Journal article
Title: Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling
Author: Pitson, S.
Xia, P.
Leclercq, T.
Moretti, P.
Zebol, J.
Lynn, H.
Wattenberg, B.
Vadas, M.
Citation: Journal of Experimental Medicine, 2005; 201(1):49-54
Publisher: Rockefeller Univ Press
Issue Date: 2005
ISSN: 0022-1007
1540-9538
Statement of
Responsibility: 
Stuart M. Pitson, Pu Xia, Tamara M. Leclercq, Paul A.B. Moretti, Julia R. Zebol, Helen E. Lynn, Binks W. Wattenberg, and Mathew A. Vadas
Abstract: Sphingosine kinase (SK) 1 catalyzes the formation of the bioactive lipid sphingosine 1-phosphate, and has been implicated in several biological processes in mammalian cells, including enhanced proliferation, inhibition of apoptosis, and oncogenesis. Human SK (hSK) 1 possesses high instrinsic catalytic activity which can be further increased by a diverse array of cellular agonists. We have shown previously that this activation occurs as a direct consequence of extracellular signal–regulated kinase 1/2–mediated phosphorylation at Ser225, which not only increases catalytic activity, but is also necessary for agonist-induced translocation of hSK1 to the plasma membrane. In this study, we report that the oncogenic effects of overexpressed hSK1 are blocked by mutation of the phosphorylation site despite the phosphorylation-deficient form of the enzyme retaining full instrinsic catalytic activity. This indicates that oncogenic signaling by hSK1 relies on a phosphorylation-dependent function beyond increasing enzyme activity. We demonstrate, through constitutive localization of the phosphorylation-deficient form of hSK1 to the plasma membrane, that hSK1 translocation is the key effect of phosphorylation in oncogenic signaling by this enzyme. Thus, phosphorylation of hSK1 is essential for oncogenic signaling, and is brought about through phosphorylation-induced translocation of hSK1 to the plasma membrane, rather than from enhanced catalytic activity of this enzyme.
Keywords: Cells, Cultured
Cell Membrane
Humans
Cell Transformation, Neoplastic
Phosphotransferases (Alcohol Group Acceptor)
DNA Primers
Fluorescent Antibody Technique
Transfection
Polymerase Chain Reaction
Signal Transduction
Apoptosis
Cell Proliferation
Protein Transport
Phosphorylation
Mutation
Rights: © The Rockefeller University Press
DOI: 10.1084/jem.20040559
Appears in Collections:Aurora harvest 2
Molecular and Biomedical Science publications

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