Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form
As of April 1st VIVO Scientific Profiles will no longer updated for faculty, and the link to VIVO will be removed from the library website. Faculty profile pages will continue to be updated via Interfolio. VIVO will continue being used behind the scenes to update graduate student profiles. Please contact helplib@scripps.edu if you have questions.
How to download citations from VIVO | Alternative profile options

Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Don, A. S.
  • Martinez-Lamenca, C.
  • Webb, W. R.
  • Proia, R. L.
  • Roberts, Edward
  • Rosen, Hugh

publication date

  • May 2007

journal

  • Journal of Biological Chemistry  Journal

abstract

  • The clinical immunosuppressant FTY720 is a sphingosine analogue that, once phosphorylated by sphingosine kinase 2 (Sphk2), is an agonist of multiple receptor subtypes for sphingosine 1-phosphate. Short exposures to FTY720 afford long term protection in lymphoproliferative and autoimmune disease models, presumably by inducing apoptosis in subsets of cells essential for pathogenesis. Sphingosine itself is pro-apoptotic, and apoptosis induced with FTY720 or sphingosine is thought to proceed independently of their phosphorylation. Following chemical mutagenesis of Jurkat cells we isolated mutants that are selectively resistant to FTY720 analogue AAL(R), as well as natural sphingolipid bases, including sphingosine. Cells lacking functional Sphk2 were resistant to apoptosis induced with AAL(R), indicating that apoptosis proceeds through AAL(R) phosphorylation. Phosphorylation of AAL(R) was also required for induction of lymphocyte apoptosis in mice, as apoptosis was not induced with the non-phosphorylatable chiral analogue, AAL(S). Apoptosis was induced in the spleen but not the thymus of mice administered 1 mg/kg AAL(R), correlating with levels of AAL(R)-phosphate (AFD(R)) in organ extracts. AFD(R) did not induce apoptosis when added to the cell culture medium, indicating that it induces apoptosis through an intracellular target. NBD-labeled AAL(R) localized to the endoplasmic reticulum, and AAL(R) treatment resulted in elevated cytosolic calcium, Bax redistribution from cytosol to mitochondrial and endoplasmic reticulum membranes, and caspase-independent mitochondrial permeabilization in Jurkat cells. We therefore describe an apoptotic pathway triggered by intracellular accumulation of sphingolipid base phosphates and suggest that sphingoid base substrates for Sphk2 acting intracellularly could be useful in the treatment of lymphoproliferative diseases.

subject areas

  • Animals
  • Apoptosis
  • Autoimmune Diseases
  • Calcium Signaling
  • Caspases
  • Cell Membrane Permeability
  • Drug Resistance, Neoplasm
  • Endoplasmic Reticulum
  • Fingolimod Hydrochloride
  • HeLa Cells
  • Humans
  • Immunosuppressive Agents
  • Jurkat Cells
  • Lymphoproliferative Disorders
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Mutagenesis
  • Organ Specificity
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Propylene Glycols
  • Protein Transport
  • Receptors, Lysosphingolipid
  • Sphingolipids
  • Sphingosine
  • Spleen
  • Thymus Gland
  • bcl-2-Associated X Protein
scroll to property group menus

Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M609124200

PubMed ID

  • 17400555
scroll to property group menus

Additional Document Info

start page

  • 15833

end page

  • 15842

volume

  • 282

issue

  • 21

©2022 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support