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Sphingosine-1-phosphate phosphatases.

S M Mandala1

  • 1Department of Infectious Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA. suzanne_mandala@merck.com

Prostaglandins & Other Lipid Mediators
|April 28, 2001
PubMed
Summary

Sphingosine-1-phosphate phosphatase (SPPase) enzymes regulate cellular lipid signaling. Cloning and characterization reveal SPPases as Type 2 lipid phosphohydrolases with distinct selectivity, impacting cell survival and stress resistance.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Sphingosine-1-phosphate (S1P) is a key signaling lipid involved in proliferation, survival, and cell shape.
  • S1P acts as an extracellular ligand for G-protein-coupled receptors and potentially intracellular targets.
  • S1P is synthesized from sphingosine via sphingosine kinase and is regulated by sphingosine-1-phosphate phosphatase (SPPase).

Purpose of the Study:

  • To characterize the cloned sphingosine-1-phosphate phosphatase (SPPase) genes and their encoded enzymes.
  • To understand the enzymatic properties and substrate specificity of SPPases.
  • To investigate the role of SPPase activity in regulating intracellular S1P, sphingosine, and ceramide levels.

Main Methods:

  • Cloning of SPPase genes from yeast and mammalian cells.
  • Sequence homology analysis to classify SPPases within the Type 2 lipid phosphohydrolase family.
  • Biochemical assays to determine enzymatic activity, Mg+ independence, N-ethylmaleimide insensitivity, and substrate specificity.

Main Results:

  • SPPases are a distinct subset of Type 2 lipid phosphohydrolases with conserved active site domains but limited homology to other LPP/PAP family members.
  • SPPases exhibit high selectivity for sphingolipid substrates, unlike the broader specificity of LPP enzymes.
  • SPPase activity regulates intracellular S1P, sphingosine, and ceramide levels, influencing cell fate.
  • Loss of SPPase in yeast increases S1P and stress resistance; SPPase overexpression in mammalian cells elevates ceramide and induces apoptosis.

Conclusions:

  • SPPase enzymes play a critical role in maintaining cellular lipid homeostasis.
  • The distinct enzymatic properties of SPPases contribute to their specific roles in regulating cell signaling pathways.
  • SPPase activity is a crucial determinant of cell survival, stress response, and apoptosis.

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