Apoptotic cell extrusion depends on single-cell synthesis of sphingosine-1-phosphate by sphingosine kinase 2

2021 ◽  
Vol 1866 (4) ◽  
pp. 158888
Author(s):  
Bruno Jaime Santacreu ◽  
Daniela Judith Romero ◽  
Lucila Gisele Pescio ◽  
Estefanía Tarallo ◽  
Norma Beatriz Sterin-Speziale ◽  
...  
Keyword(s):  
Single Cell ◽  
Apoptotic Cell ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Cell Synthesis ◽  
Cell Extrusion

scholarly journals Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 667-676 ◽  
Author(s):  
Yapeng Gu ◽  
Tetyana Forostyan ◽  
Roger Sabbadini ◽  
Jody Rosenblatt
Keyword(s):  
Stem Cells ◽  
Epithelial Cell ◽  
Kinase Activity ◽  
Apoptotic Cell ◽  
Sphingosine Kinase ◽  
Live Cells ◽  
Sphingosine 1 Phosphate ◽  
A Cell ◽  
Dying Cells ◽  
Cell Extrusion

To maintain an intact barrier, epithelia eliminate dying cells by extrusion. During extrusion, a cell destined for apoptosis signals its neighboring cells to form and contract a ring of actin and myosin, which squeezes the dying cell out of the epithelium. Here, we demonstrate that the signal produced by dying cells to initiate this process is sphingosine-1-phosphate (S1P). Decreasing S1P synthesis by inhibiting sphingosine kinase activity or by blocking extracellular S1P access to its receptor prevented apoptotic cell extrusion. Extracellular S1P activates extrusion by binding the S1P2 receptor in the cells neighboring a dying cell, as S1P2 knockdown in these cells or its loss in a zebrafish mutant disrupted cell extrusion. Because live cells can also be extruded, we predict that this S1P pathway may also be important for driving delamination of stem cells during differentiation or invasion of cancer cells.

Sphingosine kinase 2 (Sphk2) regulates platelet biogenesis by providing intracellular sphingosine 1-phosphate (S1P)

Blood ◽  
2013 ◽  
Vol 122 (5) ◽  
pp. 791-802 ◽  
Author(s):  
Lin Zhang ◽  
Nicole Urtz ◽  
Florian Gaertner ◽  
Kyle R. Legate ◽  
Tobias Petzold ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Platelet Production ◽  
Sphingosine Kinase 2 ◽  
Key Points ◽  
New Strategy ◽  
Sphingosine 1 Phosphate ◽  
Expression And Activity

Key Points Sphk2 provides a source of intracellular S1P that tightly controls thrombopoiesis by regulating SFK expression and activity in MKs. Modulation of intracellular S1P by regulating Sphk2 may provide a new strategy to enhance platelet production in patients with thrombocytopenia.

scholarly journals A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection

2011 ◽  
Vol 106 (6) ◽  
pp. 1341-1353 ◽  
Author(s):  
Ludovic Gomez ◽  
Melanie Paillard ◽  
Megan Price ◽  
Qun Chen ◽  
Geoffrey Teixeira ◽  
...  
Keyword(s):  
Cell Survival ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate

scholarly journals Sphingosine Kinase 2 associates with the nsP3 of chikungunya virus and is required for replication

2020 ◽  
Author(s):  
Opeoluwa O. Oyewole ◽  
St Patrick Reid
Keyword(s):  
Viral Replication ◽  
Chikungunya Virus ◽  
Protein Production ◽  
Sphingosine Kinase ◽  
Lipid Kinase ◽  
Replication Complex ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Viral Replication Complex ◽  
Genetic Targeting

AbstractSphingosine kinase 2 (SK2) is a lipid kinase that catalyzes the production of sphingosine-1-phosphate (S1P) from sphingosine. Previously, we have shown that SK2 is recruited to the viral replication complex (VRC) early during chikungunya virus (CHIKV) infection. In the present study, we demonstrate that SK2 is required for viral replication and protein production. Treatment with a SK2 inhibitor significantly impaired the function of a CHIKV replicon. Similarly, compound treatment or genetic targeting resulted in impaired viral protein production. Mechanistically, we demonstrate that CHIKV nsP3 binds to SK2. Association of nsP3 with SK2 was mediated, in part, through the FGDF motifs within the hypervariable domain (HVD) of nsP3. In a competition assay, SK2 competed with G3BP for binding to nsP3. Collectively, these results extend our previous findings and identify SK2 as a CHIKV host factor recruited by nsP3.

scholarly journals SphK2/S1P Promotes Metastasis of Triple-Negative Breast Cancer Through the PAK1/LIMK1/Cofilin1 Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Weiwei Shi ◽  
Ding Ma ◽  
Yin Cao ◽  
Lili Hu ◽  
Shuwen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Tnbc Cell ◽  
Sphingosine 1 Phosphate

BackgroundTriple-negative breast cancer (TNBC) features a poor prognosis, which is partially attributed to its high metastatic rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, and HER-2, respectively) in cancer. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalyst sphingosine-1-phosphate (S1P) in TNBC metastasis and the effect of the SphK2-specific inhibitor ABC294640 on TNBC metastasis.MethodsThe function of SphK2 and S1P in TNBC cell metastasis was evaluated using transwell migration and wound-healing assays. The molecular mechanism of SphK2/S1P mediating TNBC metastasis was investigated using Western blot, histological examination, and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in an in vivo TNBC lung metastatic model.ResultsSphingosine kinase 2 promoted TNBC cell migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis in vivo. p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1), and Cofilin1 were the downstream signaling molecules of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P-induced TNBC cell migration.ConclusionSphingosine kinase 2/sphingosine-1-phosphate promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 inhibits TNBC metastasis in vivo and could be developed as a novel agent for the clinical treatment of TNBC.

Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1454-1458 ◽  
Author(s):  
Barbara Zemann ◽  
Bernd Kinzel ◽  
Matthias Müller ◽  
Roland Reuschel ◽  
Diana Mechtcheriakova ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Phase 2 ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Potent Agonist ◽  
Immunomodulatory Drug ◽  
Secondary Lymphoid Organs ◽  
Deficient Mice

FTY720, a potent immunomodulatory drug in phase 2/3 clinical trials, induces rapid and reversible sequestration of lymphocytes into secondary lymphoid organs, thereby preventing their migration to sites of inflammation. As prerequisite for its function, phosphorylation of FTY720 to yield a potent agonist of the sphingosine-1-phosphate receptor S1P1 is required in vivo, catalyzed by an as-yet-unknown kinase. Here, we report on the generation of sphingosine kinase 2 (SPHK2) knockout mice and demonstrate that this enzyme is essential for FTY720 phosphate formation in vivo. Consequently, administration of FTY720 does not induce lymphopenia in SPHK2-deficient mice. After direct dosage of FTY720 phosphate, lymphopenia is only transient in this strain, indicating that SPHK2 is constantly required to maintain FTY720 phosphate levels in vivo.

Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells

Blood ◽  
2010 ◽  
Vol 115 (17) ◽  
pp. 3531-3540 ◽  
Author(s):  
Andreas Weigert ◽  
Sarah Cremer ◽  
Martina Victoria Schmidt ◽  
Andreas von Knethen ◽  
Carlo Angioni ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Cell ◽  
Apoptotic Cell ◽  
Sphingosine Kinase ◽  
Relevant Information ◽  
Lipid Mediator ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Sphingosine Kinase 2 ◽  
Caspase 1

Abstract Execution of physiologic cell death known as apoptosis is tightly regulated and transfers immunologically relevant information. This ensures efficient clearance of dying cells and shapes the phenotype of their “captors” toward anti-inflammatory. Here, we identify a mechanism of sphingosine-1-phosphate production by apoptotic cells. During cell death, sphingosine kinase 2 (SphK2) is cleaved at its N-terminus in a caspase-1–dependent manner. Thereupon, a truncated but enzymatically active fragment of SphK2 is released from cells. This step is coupled to phosphatidylserine exposure, which is a hallmark of apoptosis and a crucial signal for phagocyte/apoptotic cell interaction. Our data link signaling events during apoptosis to the extracellular production of a lipid mediator that affects immune cell attraction and activation.

Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo

2015 ◽  
Vol 117 (4) ◽  
pp. 376-387 ◽  
Author(s):  
Nicole Urtz ◽  
Florian Gaertner ◽  
Marie-Luise von Bruehl ◽  
Sue Chandraratne ◽  
Faridun Rahimi ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate
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