Plasmin induces Cyr61 gene expression in fibroblasts via protease-activated receptor-1 and p44/42 mitogen-activated protein kinase-dependent signaling pathway.
OBJECTIVE
The plasminogen system has been proposed to participate in vascular remodeling and angiogenesis. Although plasmin-mediated proteolysis could contribute these processes, proteolytic targets for plasmin and their downstream effector molecules are yet to be fully defined. The aim of the present study was to elucidate potential mechanisms by which plasmin affects various cellular processes.


RESULTS
Plasmin upregulated the expression of Cyr61, a growth factor-like gene that has been implicated in cell proliferation, adhesion, and migration. Plasmin-induced gene expression is dependent on its proteolytic activity and requires its binding to cells. Studies that used wild-type fibroblasts and fibroblasts derived from PAR-1- and PAR-2-deficient mice showed that plasmin induced Cyr61 gene expression in wild-type fibroblasts and PAR-2-deficient cells but not in PAR-1-deficient cells. Consistent with this, plasmin induced the activation of p44/42 mitogen-activated protein kinase in wild-type, PAR-2 -/- cells but not in PAR-1 -/- cells. In contrast with thrombin, plasmin failed to induce Ca2+ signaling in fibroblasts.


CONCLUSIONS
Plasmin induced an angiogenic and wound-healing promoter, Cyr61, in fibroblasts through activation of PAR-1. Plasmin-induced Cyr61 expression is mediated via the p44/42 mitogen-activated protein kinase pathway independent of Ca2+ signaling.
Pendurthi
Usha R
UR
Biomedical Research, The University of Texas Health Center at Tyler, Tex 75708, USA. usha.pendurthi@uthct.edu
Ngyuen
Mylinh
M
Andrade-Gordon
Patricia
P
Petersen
Lars C
LC
Rao
L Vijaya Mohan
LV
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002460:Cell Line; D055515:Cysteine-Rich Protein 61; D003593:Cytoplasm / Q000737:chemistry / Q000201:enzymology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005341:Fibrinolysin / Q000502:physiology*; D005347:Fibroblasts / Q000737:chemistry* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006133:Growth Substances / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013917:Thrombin / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
D002070:Butadienes; C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; D029742:Caenorhabditis elegans Proteins; D055515:Cysteine-Rich Protein 61; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009570:Nitriles; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C113580:U 0126; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin; D005341:Fibrinolysin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium