Plasminogen/plasmin regulates c-fos and egr-1 expression via the MEK/ERK pathway.
In this study, we showed that plasminogen (Plg) and plasmin (Pla) bind to lysine-binding sites on cell surface and trigger a signaling pathway that activates the mitogen-activated protein kinase (MAPK) MEK and ERK1/2, which in turn leads to the expression of the primary response genes c-fos and early growth response gene egr-1. Our data show that the Plg/Pla-stimulated steady-state mRNA levels of both genes reached a maximum by 30 min and then returned to basal levels by 1h. The gene induction was sensitive to both pharmacological and genetic inhibition of MEK. Leupeptin, a serine protease inhibitor, suppressed Pla but not Plg-induced c-fos and egr-1 expression, emphasizing the role played by the serine protease activity associated with Pla. Pre-incubation with cholera toxin completely blocked the Plg/Pla-induced gene expression, suggesting that another signaling pathway, which recruits G protein-coupled receptors, may also be involved. Furthermore, Plg/Pla also stimulated AP-1 and EGR-1 DNA-binding activities, which were abrogated by pharmacological inhibition of MEK. Altogether, these results suggest that Plg/Pla stimulates c-fos and egr-1 expression via activation of the MEK/ERK pathway.
De Sousa
Lirlândia P
LP
Grupo de Transdução de Sinal, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais, Brazil.
Brasil
Bruno S A F
BS
Silva
Breno M
BM
Freitas
Marcelo H A
MH
Nogueira
Sarah V
SV
Ferreira
Paulo C P
PC
Kroon
Erna G
EG
Bonjardim
Cláudio A
CA
D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002772:Cholera Toxin / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D005341:Fibrinolysin / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D005799:Genes, Dominant; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D007976:Leupeptins / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D010958:Plasminogen / Q000502:physiology*; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D005419:Flavonoids; D017874:Immediate-Early Proteins; D007976:Leupeptins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D012313:RNA; D010958:Plasminogen; D004247:DNA; D002772:Cholera Toxin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012697:Serine Endopeptidases; D005341:Fibrinolysin; C032854:leupeptin; D008239:Lysine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one