Document Detail

Regulation of cell migration by sphingomyelin synthases: sphingomyelin in lipid rafts decreases responsiveness to signaling by the CXCL12/CXCR4 pathway.
MedLine Citation:
PMID:  22688512     Owner:  NLM     Status:  MEDLINE    
Sphingomyelin synthase (SMS) catalyzes the formation of sphingomyelin, a major component of the plasma membrane and lipid rafts. To investigate the role of SMS in cell signaling and migration induced by binding of the chemokine CXCL12 to CXCR4, we used mouse embryonic fibroblasts deficient in SMS1 and/or SMS2 and examined the effects of SMS deficiency on cell migration. SMS deficiency promoted cell migration through a CXCL12/CXCR4-dependent signaling pathway involving extracellular signal-regulated kinase (ERK) activation. In addition, SMS1/SMS2 double-knockout cells had heightened sensitivity to CXCL12, which was significantly suppressed upon transfection with the SMS1 or SMS2 gene or when they were treated with exogenous sphingomyelin but not when they were treated with the SMS substrate ceramide. Notably, SMS deficiency facilitated relocalization of CXCR4 to lipid rafts, which form platforms for the regulation and transduction of receptor-mediated signaling. Furthermore, we found that SMS deficiency potentiated CXCR4 dimerization, which is required for signal transduction. This dimerization was significantly repressed by sphingomyelin treatment. Collectively, our data indicate that SMS-derived sphingomyelin lowers responsiveness to CXCL12, thereby reducing migration induced by this chemokine. Our findings provide the first direct evidence for an involvement of SMS-generated sphingomyelin in the regulation of cell migration.
Satoshi Asano; Kazuyuki Kitatani; Makoto Taniguchi; Mayumi Hashimoto; Kota Zama; Susumu Mitsutake; Yasuyuki Igarashi; Hiroyuki Takeya; Junzo Kigawa; Akira Hayashi; Hisanori Umehara; Toshiro Okazaki
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-11
Journal Detail:
Title:  Molecular and cellular biology     Volume:  32     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-30     Completed Date:  2012-10-16     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3242-52     Citation Subset:  IM    
Division of Clinical Laboratory Medicine, Tottori University, Yonago, Japan.
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MeSH Terms
Cell Movement
Chemokine CXCL12 / metabolism*
Extracellular Signal-Regulated MAP Kinases / metabolism
Fibroblasts / cytology
Gene Expression Regulation*
Lipids / chemistry
Membrane Microdomains / chemistry
Models, Biological
Receptors, CXCR4 / metabolism*
Signal Transduction
Sphingomyelins / metabolism*
Reg. No./Substance:
0/CXCL12 protein, human; 0/CXCR4 protein, human; 0/CXCR4 protein, mouse; 0/Chemokine CXCL12; 0/Cxcl12 protein, mouse; 0/Lipids; 0/Receptors, CXCR4; 0/Sphingomyelins; EC Signal-Regulated MAP Kinases

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