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Sphingosine Kinase Type 1 Induces G12/13-Mediated Stress Fiber

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Sphingosine Kinase Type 1 Induces G12/13-Mediated Stress Fiber THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 47, Issue of November 21, pp. 46452–46460, 2003 Printed in U.S.A. Sphingosine Kinase Type 1 Induces G12/13-mediated Stress Fiber Formation, yet Promotes Growth and Survival Independent of G Protein-coupled Receptors* Received for publication, August 7, 2003, and in revised form, September 3, 2003 Published, JBC Papers in Press, September 8, 2003, DOI 10.1074/jbc.M308749200 Ana Olivera‡, Hans M. Rosenfeldt§, Meryem Bektas§¶, Fang Wang§, Isao Ishiiʈ, Jerold Chun**‡‡, Sheldon Milstien§§, and Sarah Spiegel§¶¶ From the ‡Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, and the §§Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland 20892, the §Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0614, the ʈDepartment of Molecular Genetics, National Institute of Neuroscience, Tokyo 187-8502, Japan, and the **Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037 Sphingosine 1-phosphate (S1P) is the ligand for a family mammals, has been linked to a wide spectrum of biological pro- of specific G protein-coupled receptors (GPCRs) that reg- cesses, among which cell growth, survival, and motility are prom- ulate a wide variety of important cellular functions, in- inent (1, 2). S1P is formed by sphingosine kinase (SphK), a highly cluding growth, survival, cytoskeletal rearrangements, conserved enzyme that is activated by numerous stimuli (1, 3). and cell motility. However, whether it also has an intra- The most well known actions of S1P are mediated by binding cellular function is still a matter of great debate. Overex- to a family of specific G protein-coupled receptors (GPCRs). To pression of sphingosine kinase type 1, which generated date, five members, EDG-1/S1P1, EDG-5/S1P2, EDG-3/S1P3, S1P, induced extensive stress fibers and impaired forma- EDG-6/S1P4, and EDG-8/S1P5, have been identified (1, 2, 4, 5). tion of the Src-focal adhesion kinase signaling complex, S1P receptors (S1PRs) are differentially expressed; coupled to a with consequent aberrant focal adhesion turnover, lead- variety of G proteins; and regulate angiogenesis, vascular mat- ing to inhibition of cell locomotion. We have dissected uration, cardiac development, neuronal survival, and immu- biological responses dependent on intracellular S1P from nity (1, 2, 4). In particular, S1PRs have been shown to play those that are receptor-mediated by specifically blocking ␣ ␣ ␣ ␤␥ critical roles in cell migration (6–10). Activation of S1P1 or signaling of G q,G i,G 12/13, and G subunits, the G proteins that S1P receptors (S1PRs) couple to and signal S1P3 by S1P in many cell types increases directional or chemo- through. We found that intracellular S1P signaled “inside tactic migration (6, 8, 10–12), whereas binding to S1P2 abol- ishes chemotaxis and membrane ruffling (13). out” through its cell-surface receptors linked to G12/13- mediated stress fiber formation, important for cell motil- Downstream of heterotrimeric G proteins, the S1PRs regu- ity. Remarkably, cell growth stimulation and suppression late tyrosine kinases such as focal adhesion kinase (FAK) and of apoptosis by endogenous S1P were independent of Src, which reside in focal adhesions, and the small GTPases of GPCRs and inside-out signaling. Using fibroblasts from the Rho family that are important for cytoskeletal rearrange- embryonic mice devoid of functional S1PRs, we also dem- ments (14). Whereas binding of S1P to S1P1 mediates cortical onstrated that, in contrast to exogenous S1P, intracellular actin assembly and Rac activation (8, 15), binding to S1P2 and S1P formed by overexpression of sphingosine kinase type S1P3 induces stress fiber formation and activation of Rho, and 1 promoted growth and survival independent of its S1P2 negatively regulates Rac activity (13), thereby inhibiting GPCRs. Hence, exogenous and intracellularly generated cell migration. In contrast, increasing intracellular levels of S1Ps affect cell growth and survival by divergent path- S1P in human breast cancer cells inhibits cell motility, leading ways. Our results demonstrate a receptor-independent us to suggest a possible role for intracellular S1P in inhibiting intracellular function of S1P, reminiscent of its action in cell motility independent of its receptors (16). Moreover, other yeast cells that lack S1PRs. studies further support the notion that S1P also has second messenger functions important for calcium homeostasis (17, 18), cell growth (19–21), and suppression of apoptosis (22–24). Sphingosine 1-phosphate (S1P),1 a sphingolipid metabolite In addition, expression of SphK1 in NIH 3T3 fibroblasts ele- found in organisms as diverse as plants, yeast, worms, flies, and vates intracellular levels of S1P, expedites the G1/S transition, and protects against apoptosis (21) and enhances tumor forma- * This work was supported in part by National Institutes of Health Grant CA61774 (to S. S.). The costs of publication of this article were tion in mice (25, 26). Because the involvement of S1PRs in defrayed in part by the payment of page charges. This article must these responses has not been conclusively ruled out and be- therefore be hereby marked “advertisement” in accordance with 18 cause intracellular targets of S1P have not yet been identified, U.S.C. Section 1734 solely to indicate this fact. whether S1P has direct intracellular effects remains controver- ¶ Recipient of a fellowship from the Free University of Berlin, Berlin, Germany. sial. Dissection of the intra- and extracellular actions of S1P is ‡‡ Supported by National Institutes of Health Grant MH01723. further complicated by the observation that binding of S1P to ¶¶ To whom correspondence should be addressed. Tel.: 804-828-9330; its receptors can stimulate SphK and generation of intracellu- Fax: 804-828-8999; E-mail: [email protected]. lar S1P (27). Conversely, binding of the platelet-derived growth 1 The abbreviations used are: S1P, sphingosine 1-phosphate; SphK, sphingosine kinase; GPCR, G protein-coupled receptor; EDG, endothe- factor (PDGF) to the PDGF receptor (PDGFR) activates and lial differentiation gene; S1PR, sphingosine 1-phosphate receptor; FAK, focal adhesion kinase; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; MEFs, mouse embryonic fibro- kinase; SAPK1, stress-activated protein kinase-1; JNK, c-Jun N-termi- blasts; BSA, bovine serum albumin; PBS, phosphate-buffered saline; nal kinase; PDZ-RhoGEF, PDZ domain-containing Rho guanine ex- ERK, extracellular signal-regulated kinase; GFP, green fluorescent pro- change factor; GRK2, G protein-coupled receptor kinase-2; ␤ARK, ␤-ad- tein; BrdUrd, bromodeoxyuridine; MAPK, mitogen-activated protein renergic receptor kinase; CDK2, cyclin-dependent kinase-2. 46452 This paper is available on line at http://www.jbc.org Sphingosine Kinase and S1P Signal Inside and Outside 46453 recruits SphK1 to the cell’s leading edge (28), producing S1P, sitometric scanning of the bands and integration with NIH Image software. Blots were further edited with Adobe PhotoShop Version 5.5 which spatially and temporally stimulates S1P1 in an autocrine or paracrine manner (29) that results in activation and inte- and/or Microsoft PowerPoint 2001 for Macintosh. For immunoprecipitation studies, cells were lysed in buffer A con- gration of downstream signals essential for cell locomotion (28, taining 0.5% deoxycholate and 0.1% SDS. 400 ␮g of the clarified lysates 29). Moreover, tethering of the PDGFR with S1P1 may provide were incubated with 1–2 ␮g of anti-paxillin or anti-pan-Src antibodies a platform for integrative signaling by these two types of re- at 4 °C overnight and then with protein A/G-Sepharose beads (Santa ceptors (30). On the other hand, S1P can specifically be trans- Cruz Biotechnology, Inc.) for an additional1htocapture immunocom- ported into cells by the cystic fibrosis transmembrane regula- plexes. After pelleting and washing by brief spins at 10,000 ϫ g, the ϫ tor, a member of the ATP-binding cassette transporter family beads were resuspended in 2 sample buffer, and proteins were re- solved by SDS-PAGE. (31), which could serve to terminate signaling through the Immunostaining—Cells grown on glass coverslips coated with colla- S1PRs (31) or initiate a second wave of signals acting inside the gen I (50 ␮g/ml) were incubated overnight in Dulbecco’s modified Ea- cells, making the S1P second messenger concept even more gle’s medium supplemented with 2 ␮g/ml transferrin and 20 ␮g/ml tenuous. BSA. After treatment, cells were washed with PBS, fixed in 1.8% In this study, we examined the effects of overexpression of formalin and 0.1% Triton X-100 for 30 min, and then permeabilized SphK1 and elevated intracellular S1P while simultaneously with 0.5% Triton X-100 for 10 min. Actin filaments were visualized with Alexa 488-conjugated phalloidin (Molecular Probes, Inc., Eugene, OR), blocking signaling of the heterotrimeric G proteins that S1PRs and focal complexes were visualized with antibody to paxillin, followed couple to and signal through, to dissect biological functions by staining with Texas Red-conjugated secondary antibody. After wash- dependent on intracellular S1P from those mediated by S1PRs. ing three times with PBS, coverslips were mounted on slides using an Whereas SphK1 overexpression stimulated “inside-out” signal- anti-fade kit (Molecular Probes, Inc.), and Ͼ80 cells were
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