Sphingomyelin metabolism underlies Ras excitability for efficient cell migration and chemotaxis

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  • Shin Da Young
    Laboratory of Single Molecule Biology, Department of Biological Sciences, Graduate School of Science, Osaka University Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN
  • Takagi Hiroaki
    Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN Department of Physics, School of Medicine, Nara Medical University
  • Hiroshima Michio
    Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN Laboratory of Single Molecule Biology, Graduate School of Frontier Biosciences, Osaka University
  • Matsuoka Satomi
    Laboratory of Single Molecule Biology, Department of Biological Sciences, Graduate School of Science, Osaka University Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN Laboratory of Single Molecule Biology, Graduate School of Frontier Biosciences, Osaka University PRESTO, JST
  • Ueda Masahiro
    Laboratory of Single Molecule Biology, Department of Biological Sciences, Graduate School of Science, Osaka University Laboratory for Cell Signaling Dynamics, Center for Biosystems Dynamics Research, RIKEN Laboratory of Single Molecule Biology, Graduate School of Frontier Biosciences, Osaka University

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Abstract

<p>In eukaryotic motile cells, the active Ras (Ras-GTP)-enriched domain is generated in an asymmetric manner on the cell membrane through the excitable dynamics of an intracellular signaling network. This asymmetric Ras signaling regulates pseudopod formation for both spontaneous random migration and chemoattractant-induced directional migration. While membrane lipids, such as sphingomyelin and phosphatidylserine, contribute to Ras signaling in various cell types, whether they are involved in the Ras excitability for cell motility is unknown. Here we report that functional Ras excitability requires the normal metabolism of sphingomyelin for efficient cell motility and chemotaxis. The pharmacological blockade of sphingomyelin metabolism by an acid-sphingomyelinase inhibitor, fendiline, and other inhibitors suppressed the excitable generation of the stable Ras-GTP-enriched domain. The suppressed excitability failed to invoke enough basal motility to achieve directed migration under shallow chemoattractant gradients. The fendiline-induced defects in Ras excitability, motility and stimulation-elicited directionality were due to an accumulation of sphingomyelin on the membrane, which could be recovered by exogenous sphingomyelinase or phosphatidylserine without changing the expression of Ras. These results indicate a novel regulatory mechanism of the excitable system by membrane lipids, in which sphingomyelin metabolism provides a membrane environment to ensure Ras excitation for efficient cellular motility and chemotaxis.</p><p>Key words: cell polarity, cell migration, Ras, excitability, sphingomyelin</p>

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