Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression

Guillaume Andrieu (1, 2) , Adeline Ledoux (1, 2) , Sophie Branka (1, 2) , Magalie Bocquet (1, 2) , Julia Gilhodes (3) , Thierry Walzer (4) , Kousuke Kasahara (5) , Masaki Inagaki (5) , Roger A. Sabbadini (6) , Olivier Cuvillier (1, 2) , Anastassia Hatzoglou (1, 2)

1 IPBS - Institut de pharmacologie et de biologie structurale
2 Equipe labellisée Ligue contre le Cancer
3 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
4 Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases
5 Aichi Cancer Center Research Institute
6 Lpath Inc

Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P1-5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis. Increasing the abundance of S1P promoted mitotic progression, overrode the spindle assembly checkpoint (SAC), and led to chromosome segregation defects. S1P was secreted through the transporter SPNS2 and stimulated mitosis by binding to and activating S1P5 on the extracellular side, which then activated the intracellular phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Knockdown of S1P5 prevented the S1P-induced spindle defect phenotype. RNA interference assays revealed that the mitotic kinase Polo-like kinase 1 (PLK1) was an important effector of S1P-S1P5 signaling-induced mitosis in HeLa cells. Our findings identify an extracellular signal and the downstream pathway that promotes mitotic progression and may indicate potential therapeutic targets to inhibit the proliferation of cancer cells.

Mots clés: Animals; Blotting; Western; Cell Cycle Proteins; Cell Line; Tumor; Cells; Cultured; Chromosome Segregation; HeLa Cells; Humans; Lysophospholipids; Mice; Knockout; Microscopy; Confocal; Mitosis; Phosphotransferases (Alcohol Group Acceptor); Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Receptors; Lysosphingolipid; RNA Interference; Signal Transduction; Sphingosine; Time-Lapse Imaging

Domaines: Immunologie; Bactériologie; Virologie

Guillaume Andrieu, Adeline Ledoux, Sophie Branka, Magalie Bocquet, Julia Gilhodes, et al.. Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. Science Signaling, 2017, 10 (472), ⟨10.1126/scisignal.aah4007⟩. ⟨hal-01911204⟩