Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 43, Issue 3, Pages 342-347Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2010.11.001
Keywords
Sphingosine kinase; Protein phosphatase 2A; B 'alpha; B56 alpha; PR61 alpha; PPP2R5A; Sphingosine-1-phosphate
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Funding
- Fay Fuller Foundation
- National Health and Medical Research Council of Australia [430909, 508098]
- [453512]
- [626937]
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Sphingosine kinase 1 (SK1) is an important regulator of cellular signalling that has gained recent attention as a potential target for anti-cancer therapies. SK1 activity, subcellular localization and oncogenic function are regulated by phosphorylation and dephosphorylation at Ser225. ERK1/2 have been identified as the protein kinases responsible for phosphorylation and activation of SK1. Conversely, dephosphorylation and deactivation of SK1 occurs by protein phosphatase 2A (PP2A). Active PP2A, however, is a heterotrimer, composed of tightly associated catalytic and structural subunits that can interact with an array of regulatory subunits, which are critical for determining holoenzyme substrate specificity and subcellular localization. Thus, PP2A represents a large family of holoenzyme complexes with different activities and diverse substrate specificities. To date the regulatory subunit essential for targeting PP2A to SK1 has remained undefined. Here, we demonstrate a critical role for the B'alpha (B56 alpha/PR61 alpha/PPP2R5A) regulatory subunit of PP2A in SK1 dephosphorylation. B'alpha was found to interact with the c-terminus of SK1, and reduce SK1 phosphorylation when overexpressed, while having no effect on upstream ERK1/2 activation. siRNA-mediated knockdown of B'alpha increased SK1 phosphorylation, activity and membrane localization of endogenous SM. Furthermore, overexpression of B'alpha blocked agonist-induced translocation of SK1 to the plasma membrane and abrogated SK1-induced neoplastic transformation of NIH3T3 fibroblasts. Thus, the PP2A-B'alpha holoenzyme appears to function as an important endogenous regulator of SK1. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.
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