Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling

Stuart M. Pitson, Pu Xia, Tamara M. Leclercq, Paul A B Moretti, Julia R. Zebol, Helen E. Lynn, Binks W. Wattenberg, Mathew A. Vadas

Research output: Contribution to journalArticle

196 Citations (Scopus)

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.

LanguageEnglish
Pages49-54
Number of pages6
JournalJournal of Experimental Medicine
Volume201
Issue number1
DOIs
Publication statusPublished - 3 Jan 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Pitson, Stuart M. ; Xia, Pu ; Leclercq, Tamara M. ; Moretti, Paul A B ; Zebol, Julia R. ; Lynn, Helen E. ; Wattenberg, Binks W. ; Vadas, Mathew A. / Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. In: Journal of Experimental Medicine. 2005 ; Vol. 201, No. 1. pp. 49-54.
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Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. / Pitson, Stuart M.; Xia, Pu; Leclercq, Tamara M.; Moretti, Paul A B; Zebol, Julia R.; Lynn, Helen E.; Wattenberg, Binks W.; Vadas, Mathew A.

In: Journal of Experimental Medicine, Vol. 201, No. 1, 03.01.2005, p. 49-54.

Research output: Contribution to journalArticle

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