Opposite Effects of Dihydrosphingosine 1-Phosphate and Sphingosine 1-Phosphate on Transforming Growth Factor-β/Smad Signaling Are Mediated through the PTEN/PPM1A-dependent Pathway*
- ‡Division of Rheumatology and Immunology, and §Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425
- 1 To whom correspondence should be addressed. Tel.: 843-792-7921; Fax: 843-792-7121; E-mail: trojanme{at}musc.edu.
Abstract
Transforming growth factor-β (TGF-β) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-β through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-β signaling. In contrast to S1P, dhS1P inhibits TGF-β-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-β signaling. Consequently, overexpression of PTEN abrogates TGF-β-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-β signaling pathways may play an important role in physiological and pathological TGF-β signaling.
Footnotes
-
↵2 The abbreviations used are: TGF-β, transforming growth factor-β; TGF-βRI and TGF-βRII, TGF-β recptor I and II, respectively; S1P, sphingosine 1-phosphate; dhS1P, dihydrosphingosine 1-phosphate; ECM, extracellular matrix; SK, sphingosine kinase; Ptx, pertussis toxin; PTEN, phosphatase and tensin homologue deleted on chromosome 10; HEK 293, human embryonic kidney cells; siRNA, small interfering RNA; WT, wild type.
-
↵* This work was supported, in whole or in part, by National Institutes of Health Grants P60 AR049459 and R01 AR44883 (to M. T.), R01 CA109860 (to T. H.), and P01 CA78582. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵
The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.
-
- Received March 27, 2008.
- Revision received May 14, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
