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Sphingosine kinase C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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SPHK1 and SPHK2 are encoded by different genes with some redundancy of function; genetic deletion of both Sphk1 and Sphk2, but not either alone, is embryonic lethal in mice. There are splice variants of each isoform (SphK1a-c and SphK2a, b), distinguished by their N-terminal sequences. SPHK1 and SPHK2 differ in tissue distribution, sub-cellular localisation, biochemical properties and regulation. They regulate discrete pools of S1P. Receptor stimulation induces SPHK1 translocation from the cytoplasm to the plasma membrane. SPHK1 translocation is regulated by phosphorylation/dephosphorylation, specific protein:protein interactions and interaction with specific lipids at the plasma membrane. SPHK1 is a dimeric protein, as confirmed by its crystal structure which forms a positive cluster, between protomers, essential for interaction with anionic phospholipids in the plasma membrane. SPHK2 is localised to the ER or associated with mitochondria or shuttles in/out of the nucleus, regulated by phosphorylation. Intracellular targets of nuclear S1P include the catalytic subunit of telomerase (TERT) and regulators of gene expression including histone deacetylases (HDAC 1/2) and peroxisome proliferator-activated receptor gamma (PPARγ). SPHK2 phosphorylates the pro-drug FTY720 (fingolimod, which is used to treat some forms of multiple sclerosis) to a mimic of S1P and that acts as a functional antagonist of S1P1 receptors. Inhibitors of SPHK1 and SPHK2 have therapeutic potential in many diseases.

Enzymes

SPHK1 (sphingosine kinase 1) C Show summary » More detailed page

SPHK2 (sphingosine kinase 2) C Show summary » More detailed page

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References

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NC-IUPHAR subcommittee and family contributors

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How to cite this family page

Database page citation:

Nigel J Pyne, Susan Pyne. Sphingosine kinase. Accessed on 17/06/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=787.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Enzymes. Br J Pharmacol. 174 Suppl 1: S272-S359.