Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2004-8-30
pubmed:abstractText
Plasminogen activators (tPA and uPA) are serine proteases that convert the circulating zymogen plasminogen to active plasmin and mediate fibrin degradation. These multifunctional proteins trigger various biological events such as extracellular matrix degradation, cell adhesion, migration, and proliferation, through not yet fully characterized mechanisms. We report that, in smooth muscle cells and ECV-304 carcinoma cells, tPA and ATF (the N-terminal catalytically inactive fragment of tPA) elicited DNA synthesis that requires activation of the sphingomyelin/ceramide/sphingosine-1-phosphate (Spm/Cer/S1P), signaling pathway and was blocked by D-erythro-2-(N-myristoylamino)-1-phenyl-propanol (D-MAPP) and N-N'-dimethyl sphingosine (DMS), two classical inhibitors of sphingosine-1-phosphate biosynthesis. Binding of tPA to its receptor uPAR triggered the coordinated activation of two key enzymes of the Spm/Cer/S1P pathway, the neutral sphingomyelinase and the sphingosine kinase-1 that was mediated by a common pertussis toxin (PTX)-sensitive mechanism. The tPA-induced sphingosine kinase-1 activation was mediated by Src, since it was inhibited by herbimycin A and in SrcK- cells (overexpressing a dominant negative kinase defective form of Src) and by ERK1/2 (early phase peaking at 15 min). Sphingosine kinase-1 activation was followed by a second phase of ERK1/2 phosphorylation (peaking at 120 min) and subsequent DNA synthesis, which were inhibited by D-MAPP and DMS, by anti-EGD-1 antibodies and in SrcK- cells (in which the mitogenic signaling was rescued by sphingosine-1-phosphate). Altogether, these data underline a pivotal role for the Spm/Cer/S1P pathway in the tPA-induced mitogenic signaling.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Benzoquinones, http://linkedlifedata.com/resource/pubmed/chemical/Ceramides, http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP..., http://linkedlifedata.com/resource/pubmed/chemical/Lactams, Macrocyclic, http://linkedlifedata.com/resource/pubmed/chemical/Lysophospholipids, http://linkedlifedata.com/resource/pubmed/chemical/Mitogens, http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments, http://linkedlifedata.com/resource/pubmed/chemical/Pertussis Toxin, http://linkedlifedata.com/resource/pubmed/chemical/Phosphotransferases (Alcohol Group..., http://linkedlifedata.com/resource/pubmed/chemical/Quinones, http://linkedlifedata.com/resource/pubmed/chemical/Sphingomyelins, http://linkedlifedata.com/resource/pubmed/chemical/Sphingosine, http://linkedlifedata.com/resource/pubmed/chemical/Tissue Plasminogen Activator, http://linkedlifedata.com/resource/pubmed/chemical/Urokinase-Type Plasminogen Activator, http://linkedlifedata.com/resource/pubmed/chemical/herbimycin, http://linkedlifedata.com/resource/pubmed/chemical/sphingosine 1-phosphate, http://linkedlifedata.com/resource/pubmed/chemical/sphingosine kinase
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1530-6860
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1398-400
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15231724-Benzoquinones, pubmed-meshheading:15231724-Cell Line, pubmed-meshheading:15231724-Cell Proliferation, pubmed-meshheading:15231724-Ceramides, pubmed-meshheading:15231724-Enzyme Activation, pubmed-meshheading:15231724-Extracellular Signal-Regulated MAP Kinases, pubmed-meshheading:15231724-Lactams, Macrocyclic, pubmed-meshheading:15231724-Lysophospholipids, pubmed-meshheading:15231724-MAP Kinase Signaling System, pubmed-meshheading:15231724-Mitogens, pubmed-meshheading:15231724-Myocytes, Smooth Muscle, pubmed-meshheading:15231724-Peptide Fragments, pubmed-meshheading:15231724-Pertussis Toxin, pubmed-meshheading:15231724-Phosphorylation, pubmed-meshheading:15231724-Phosphotransferases (Alcohol Group Acceptor), pubmed-meshheading:15231724-Quinones, pubmed-meshheading:15231724-Signal Transduction, pubmed-meshheading:15231724-Sphingomyelins, pubmed-meshheading:15231724-Sphingosine, pubmed-meshheading:15231724-Tissue Plasminogen Activator, pubmed-meshheading:15231724-Up-Regulation, pubmed-meshheading:15231724-Urokinase-Type Plasminogen Activator
pubmed:year
2004
pubmed:articleTitle
The sphingomyelin/ceramide pathway is involved in ERK1/2 phosphorylation, cell proliferation, and uPAR overexpression induced by tissue-type plasminogen activator.
pubmed:affiliation
Inserm U-466, CHU Rangueil, Toulouse, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't