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Dihydrosphingosine 1‐phosphate stimulates MMP1 gene expression via activation of ERK1/2‐Ets1 pathway in human fibroblasts
Author(s) -
Bu Shizhong,
Yamanaka Masayoshi,
Pei Huiping,
Bielawska Alicja,
Bielawski Jacek,
Hannun Yusuf A.,
Obeid Lina,
Trojanowska Maria
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4646fje
Subject(s) - sphingosine kinase , mmp1 , microbiology and biotechnology , sphingosine kinase 1 , sphingosine 1 phosphate , lipid signaling , chemistry , sphingosine , signal transduction , intracellular , biology , gene expression , receptor , gene , biochemistry
Sphingosine kinase (SphK) is a conserved lipid kinase that catalyzes formation of important regulators of inter‐and intracellular signaling, sphingosine‐1 phosphate (S1P), and dihydrosphingosine 1‐phosphate (dhS1P). In this study, we investigated the role of SphK1 in the regulation of expression of matrix metalloproteinase 1 (MMP1) in dermal fibroblasts, a key event in regulation of extra cellular matrix. We show that overexpression of SphK1 up‐regulated MMP1 protein, MMP1 mRNA, and MMP1 promoter activity, and this action of SphK1 required activation of the ERK1/2‐Ets1 and NF‐kB pathways. Furthermore, experiments using SphK1 specific siRNA demonstrated that SphK1 is required for the TNF‐α stimulation of MMP1. Additional data revealed a specific role of dhS1P, and not S1P, as a mediator of SphK1dependent activation of ERK1/2 and up‐regulation of MMP1. The stimulatory effect of dhS1P was sensitive to pertussis toxin, suggesting a possible involvement of a G‐protein‐coupled receptor. In contrast, S1P, but not dhS1P, stimulated the induction of COX‐2, which demonstrated selective actions of these two closely related bioactive lipids. In conclusion, this study describes a novel mode of SphK1 signaling through generation of dhS1P with a key role in mediating transcriptional responses to TNF‐α. This is the first report of selective function of dhS1P as compared with the better studied S1P.