A new model for regulation of sphingosine kinase 1 translocation to the plasma membrane in breast cancer cells.
Animals
Breast Neoplasms
/ genetics
Cell Membrane
/ metabolism
Female
Humans
Lysophospholipids
/ metabolism
MCF-7 Cells
Membrane Microdomains
/ metabolism
Mice
Phosphotransferases (Alcohol Group Acceptor)
/ chemistry
Protein Conformation
Protein Multimerization
Protein Transport
Sphingosine
/ analogs & derivatives
Sphingosine-1-phosphate (S1P)
enzyme mechanism
fluorescence
lipid signaling
mutagenesis in vitro
plasma membrane
structural biology
translocation
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
Historique:
received:
08
02
2021
revised:
01
04
2021
accepted:
14
04
2021
pubmed:
19
4
2021
medline:
24
8
2021
entrez:
18
4
2021
Statut:
ppublish
Résumé
The translocation of sphingosine kinase 1 (SK1) to the plasma membrane (PM) is crucial in promoting oncogenesis. We have previously proposed that SK1 exists as both a monomer and dimer in equilibrium, although it is unclear whether these species translocate to the PM via the same or different mechanisms. We therefore investigated the structural determinants involved to better understand how translocation might potentially be targeted for therapeutic intervention. We report here that monomeric WT mouse SK1 (GFP-mSK1) translocates to the PM of MCF-7L cells stimulated with carbachol or phorbol 12-myristate 13-acetate, whereas the dimer translocates to the PM in response to sphingosine-1-phosphate; thus, the equilibrium between the monomer and dimer is sensitive to cellular stimulus. In addition, carbachol and phorbol 12-myristate 13-acetate induced translocation of monomeric GFP-mSK1 to lamellipodia, whereas sphingosine-1-phosphate induced translocation of dimeric GFP-mSK1 to filopodia, suggesting that SK1 regulates different cell biological processes dependent on dimerization. GFP-mSK1 mutants designed to modulate dimerization confirmed this difference in localization. Regulation by the C-terminal tail of SK1 was investigated using GFP-mSK1 truncations. Removal of the last five amino acids (PPEEP) prevented translocation of the enzyme to the PM, whereas removal of the last ten amino acids restored translocation. This suggests that the penultimate five amino acids (SRRGP) function as a translocation brake, which can be released by sequestration of the PPEEP sequence. We propose that these determinants alter the arrangement of N-terminal and C-terminal domains in SK1, leading to unique surfaces that promote differential translocation to the PM.
Identifiants
pubmed: 33865856
pii: S0021-9258(21)00463-4
doi: 10.1016/j.jbc.2021.100674
pmc: PMC8135045
pii:
doi:
Substances chimiques
Lysophospholipids
0
sphingosine 1-phosphate
26993-30-6
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
sphingosine kinase
EC 2.7.1.-
Sphingosine
NGZ37HRE42
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100674Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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