title: Sphingosine 1-phosphate, present in serum-derived lipoproteins, activates matriptase.
abstract: We describe here a novel biological function of sphingosine 1-phosphate (S1P): the activation of a serine protease, matriptase. Matriptase is a type II integral membrane serine protease, expressed on the surface of a variety of epithelial cells; it may play an important role in tissue remodeling. We have previously reported that the activation of matriptase is regulated by serum. We have now identified the bioactive component from serum. First, the activity was observed to co-purify with lipoproteins by conventional liquid chromatography and immunoaffinity chromatography. The ability of lipoproteins to induce the activation of matriptase was further confirmed with commercial preparations of low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Next, we observed that the bioactive component of LDL is associated with the phospholipid components of LDL. Fractionation of lipid components of LDL by thin layer chromatography (TLC) revealed that the bioactive component of LDL comigrates with S1P. Nanomolar concentrations of commercially obtained S1P were then observed to induce the rapid activation of matriptase on the surfaces of nontransformed human mammary epithelial cells. Other structurally related sphingolipids, including dihydro-S1P, ceramide 1-phosphates, and sphingosine phosphocholine as well as lysophosphatidic acid, can also induce the activation of matriptase, but at significantly higher concentrations than S1P. Furthermore, S1P-dependent matriptase activation is dependent on Ca(2+) but not via G(i) protein-coupled receptors. Our results demonstrate that bioactive phospholipids can function as nonprotein activators of a cell surface protease, suggesting a possible mechanistic link between S1P and normal and possibly pathologic tissue remodeling.
authors.affiliation: Lombardi Cancer Center and Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Benaud
authors.forename: Michael
authors.initials: M
authors.lastname: Oberst
authors.forename: John P
authors.initials: JP
authors.lastname: Hobson
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Robert B
authors.initials: RB
authors.lastname: Dickson
authors.forename: Chen-Yong
authors.initials: CY
authors.lastname: Lin
mesh_terms: D015153:Blotting, Western; D001940:Breast / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D002846:Chromatography, Affinity; D002853:Chromatography, Liquid; D002855:Chromatography, Thin Layer; D016895:Culture Media, Serum-Free / Q000494:pharmacology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008246:Lysophospholipids; D008856:Microscopy, Fluorescence; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D012694:Serine / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D002518:Ceramides; D016895:Culture Media, Serum-Free; D004983:Ethanolamines; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D008246:Lysophospholipids; D010743:Phospholipids; D010566:Virulence Factors, Bordetella; C065576:ceramide 1-phosphate; C060504:dihydrosphingosine 1-phosphate; C060506:sphingosine 1-phosphate; D012694:Serine; D013498:Suramin; D012697:Serine Endopeptidases; C485595:matriptase; C485596:ST14 protein, human; D014357:Trypsin; D013110:Sphingosine; C007369:2-diethylaminoethanol; D002118:Calcium