Stimulation of nuclear sphingosine kinase activity by platelet‐derived growth factor

Kleuser, Burkhard; Maceyka, Michael; Milstien, Sheldon; Spiegel, Sarah

doi:10.1016/s0014-5793(01)02697-7

Cited by 60 publications

(52 citation statements)

References 35 publications

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“…3, G and H). SphK1 has been shown to be distributed in both cytosolic and nuclear compartments in cultured cells (18,22), but our findings indicate that the increase in staining is primarily cytosolic in late pregnancy.…”

Section: Resultscontrasting

confidence: 68%

Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences

Jeng¹,

Suarez²,

Izban³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Jeng YJ, Suarez VR, Izban MG, Wang HQ, Soloff MS. Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences. Am J Physiol Endocrinol Metab 292: E1110 -E1121, 2007. First published December 12, 2006; doi:10.1152/ajpendo.00373.2006.-Sphingosine 1-phosphate (Sph-1-P), a product of sphingomyelin metabolism, can act via a family of cognate G protein-coupled receptors or as an intracellular second messenger for agonists acting through their membrane receptors. In view of the general growth promoting and developmental effects of Sph-1-P on target cells, we hypothesized that it plays a role in adaptation of the uterus to pregnancy. We analyzed its potential role and that of the related lysophospholipid lysophosphatidic acid in the pregnant rat uterus by examining changes in mRNA levels of cognate receptors and enzymes involved in their turnover. Of these, only sphingosine kinase-1 (SphK1) was markedly changed (ϳ30-fold increase), being localized in the glandular epithelium, vasculature, and the myometrium. Uterine SphK1 mRNA and protein levels paralleled those of serum progesterone, and treatment with progesterone or an antagonist elevated or reduced SphK1 mRNA expression, respectively. Progesterone also increased SphK1 mRNA steady-state levels in a rat myometrial/leiomyoma cell line (ELT3). Overexpressing human SphK1 in these cells resulted in increased levels of the cell cycle regulator cyclin D1 and increased myosin light-chain phosphorylation. Ectopic expression of SphK1 also resulted in increased proliferation rates, possibly in conjunction with increased cyclin D1 expression. These studies suggest that the uterine expression of SphK1 mediates processes involved in growth and differentiation of uterine tissues during pregnancy. ELT3 cells; myosin light-chain phosphorylation; cyclin D1; lysophospholipids; sphingosine 1-phosphate; sphingosine-1-phosphate lyase THE BIOACTIVE LYSOPHOSPHOLIPIDS sphingosine 1-phosphate (Sph-1-P) and lysophosphatidic acid (LPA) are growth factors that act through a family of G protein-coupled receptors (GPCRs), S1P 1 through S1P 5 and LPA 1 through LPA 4 , respectively (25), causing a broad array of effects on target cells, including cell proliferation, survival, migration, adhesion molecule expression, and morphogenesis (26,31,44,47,52). Sph-1-P also plays a role in vasculogenesis in the mouse embryo (4, 27). Both lysophospholipids increase myosin lightchain phosphorylation in platelets and endothelial cells (10, 37) by inhibiting myosin light-chain phosphatase (43). They also stimulate DNA synthesis in human myometrial cells in primary culture (20,32). Platelets are the major source of circulating Sph-1-P and LPA, releasing the lysophospholipids in response to prothrombotic stimuli (47, 54). Circulating Sph-1-P also arises by constitutive secretion by cells of hemangioblastic lineage, such as monocytes, and by mast, endothelial, and red blood cells (54).Intracellular Sph-1-P is synthesized by a variety of cell types and acts as a...

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Section: Resultscontrasting

confidence: 68%

Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences

Jeng¹,

Suarez²,

Izban³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…In this context, Kleuser et al (2001) showed that in Swiss 3T3 fibroblasts overexpressing green fluorescence protein-coupled SK-1, the enzyme was equally localised in the cytoplasm and in the nucleus and that the nuclear fraction of SK-1 was activated upon PDGF stimulation. Indeed, sequence analysis of SK-1 revealed a nuclear export signal that directs export of SK-1 from the nucleus to the cytoplasm and suggests constant 'shuttling' of the enzyme (Inagaki et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

Hofmann

Ren

Schwalm

et al. 2008

BCHM

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Sphingosine kinases (SKs) are key enzymes regulating the production of sphingosine-1-phosphate (S1P), which determines important cell responses including cell growth and death. Here we show that renal mesangial cells isolated from wild-type, SK-1 -/-, and SK-2 -/-mice show a differential response to apoptotic stimuli. Wildtype mesangial cells responded to staurosporine with increased DNA fragmentation and caspase-3 processing, which was enhanced in SK-1 -/-cells. In contrast, SK-2 -/-cells were highly resistant to staurosporine-induced apoptosis. Furthermore, the basal phosphorylation and activity of the anti-apoptotic protein kinase B (PKB) and of its substrate Bad were decreased in SK-1 -/-but not in SK-2 -/-cells. Upon staurosporine treatment, phosphorylation of PKB and Bad decreased in wild-type and SK-1 -/-cells, but remained high in SK-2 -/-cells. In addition, the anti-apoptotic Bcl-X L was significantly upregulated in SK-2 -/-cells, which may further contribute to the protective state of these cells. In summary, our data show that SK-1 and SK-2 have opposite effects on the capacity of mesangial cells to resist apoptotic stimuli. This is due to differential modulation of the PKB/Bad pathway and of Bcl-X L expression. Thus, subtype-selective targeting of SKs will be critical when considering these enzymes as therapeutic targets for the treatment of inflammation or cancer.

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“…Isolation of Nuclei-The separation of nuclei from cells was carried out essentially as described (13), with some modifications (14). For the preparation of cytosolic fraction, the supernatant fractions above the sucrose cushion obtained after 15,000 ϫ g step were further centrifuged at 100,000 ϫ g for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Sphingosine Kinase 2 Is a Nuclear Protein and Inhibits DNA Synthesis

Igarashi

Okada

Hayashi

et al. 2003

Journal of Biological Chemistry

386

346

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Sphingosine kinase-1 (SPHK1) is a key enzyme catalyzing the formation of an important bioactive lipid messenger, sphingosine 1-phosphate, and is implicated in the regulation of cell proliferation and antiapoptotic processes. Biological features of another isozyme SPHK2, however, remain unclear. The present studies were undertaken to characterize SPHK2 by comparison with SPHK1. When SPHK2 was transiently expressed in various cell lines, it was localized in the nuclei as well as in the cytosol, whereas SPHK1 was distributed in the cytosol but not in the nucleus. We have mapped a functional nuclear localization signal (NLS) to the N-terminal region of SPHK2. We have observed that the expression of SPHK2 in various cell types causes inhibition of DNA synthesis, resulting in the cell cycle arrest at G 1 /S phase. We have also demonstrated that an NLS mutant of SPHK2, SPHK2R93E/R94E, failed to enter the nucleus and to inhibit DNA synthesis. Moreover, a fusion protein, NLS-SPHK1, where SPHK1 was fused to the NLS sequence of SPHK2 acquired the ability to enter nuclei and inhibited DNA synthesis. These results indicate that SPHK2 localizes in the nuclei and causes inhibition of DNA synthesis, and this may affect subsequent cellular events.Sphingosine 1-phosphate (SPP) 1 is a bioactive lipid that regulates diverse biological processes such as calcium mobilization, cell growth, differentiation, survival, motility, and cytoskeletal reorganization, acting both inside and outside the cells (1, 2). Recently, SPP was identified as the ligand for a family of G protein-coupled receptors known as the endothelial differentiation gene-1 family, now collectively renamed SPP receptors (3-6), supporting a role for SPP as an extracellular ligand. However, the intracellular targets of SPP have not yet been identified.Sphingosine kinase (SPHK), the enzyme that catalyzes the phosphorylation of sphingosine, regulates the intracellular levels of SPP. Two isoforms of mammalian SPHK (SPHK1 and SPHK2) have been cloned and characterized (7,8). SPHK1 predominantly localizes in the cytosol, and its overexpression induces cell proliferation by promoting the G 1 to S transition of the cell cycle as well as by inhibiting the apoptotic response to serum deprivation or ceramide treatment (9). Several cellular proteins have recently been identified as SPHK1-interacting molecules, namely TRAF2 (10), RPK118 (11), and AKAP-related protein (12), which should help facilitate the understanding of the regulation and intracellular site of action of SPHK1.In contrast to SPHK1, little is known about the cellular actions of the other isozyme, SPHK2. In the present studies, we investigated the biological features of SPHK2. We have discovered that SPHK2 localizes in the nuclei of cells through its novel nuclear localization signal (NLS) sequence, depending on cell type and cell density. We have also demonstrated that nuclear localization of SPHK2 causes inhibition of DNA synthesis in various cell types.

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Stimulation of nuclear sphingosine kinase activity by platelet‐derived growth factor

Cited by 60 publications

References 35 publications

Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences

Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences

Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

Sphingosine Kinase 2 Is a Nuclear Protein and Inhibits DNA Synthesis

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