Urokinase-Type and Tissue-Type Plasminogen Activators as Growth Factors of Human Fibroblasts

Petro, Giuseppina De; Copeta, Alessandro; Barlati, Sergio

doi:10.1006/excr.1994.1200

Cited by 77 publications

(48 citation statements)

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“…These data are consistent with those of De Petro et al, who reported that uPA promotes proliferation of skin fibroblasts through a mechanism that required proteolytic activity. 43 These findings are also consistent with those of Tanski et al, who showed that proteolytic activity of uPA was required for stimulation of proliferation of smooth muscle cells, and that this occurred through an MEK1-dependent mechanism. 42 HGF has been shown to induce phosphorylation of ERK1/2 in a PI3K-dependent manner in myogenic cells, 44 which is consistent with the idea that uPA activates PI3K and ERK1/2 by activating HGF.…”

Section: Org Fromsupporting

confidence: 91%

Urokinase-type plasminogen activator increases hepatocyte growth factor activity required for skeletal muscle regeneration

Sisson

Nguyen

et al. 2009

Blood

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The plasminogen system plays a crucial role in the repair of a variety of tissues, including skeletal muscle. We hypothesized that urokinase-type plasminogen activator (uPA) promotes muscle regeneration by activating hepatocyte growth factor (HGF), which, in turn, stimulates proliferation of myoblasts required for regeneration. In our studies, levels of active HGF and phosphorylation of the HGF receptor c-met were increased after muscle injury in wild-type mice. Compared with wild-type animals, mice deficient in uPA (uPA ؊/؊ ) had markedly reduced HGF levels and c-met activation after muscle damage. This reduced HGF activity in uPA ؊/؊ animals was associated with decreased cell proliferation, myoblast accumulation, and new muscle fiber formation. On the other hand, HGF activity was enhanced at early time points in PAI-1 ؊/؊ mice compared with wild-type mice and the PAI-1 ؊/؊ animals exhibited accelerated muscle fiber regeneration. Furthermore, administration of exogenous uPA rescued HGF levels and muscle regeneration in uPA ؊/؊ mice, and an HGF-blocking antibody reduced HGF activity and muscle regeneration in wildtype mice. We also found that uPA promotes myoblast proliferation in vitro through its proteolytic activity, and this process was inhibited by an HGFblocking antibody. Together, our findings demonstrate that uPA promotes muscle regeneration through HGF activation and subsequent myoblast proliferation. IntroductionThe plasminogen system plays a crucial role in the repair of a variety of tissues. This extracellular serine protease cascade includes the urokinase-type plasminogen activator (uPA) and its primary inhibitor, plasminogen activator inhibitor-1 (PAI-1). The classic function of uPA is to cleave plasminogen to form active plasmin, a broad-spectrum protease with activity toward a variety of extracellular matrix molecules. 1,2 Genetic manipulations that inhibit plasminogen activation lead to impaired healing of lung, liver, kidney, and skin. [3][4][5][6] Similarly, mice deficient in uPA or plasminogen demonstrate markedly impaired muscle regeneration. [7][8][9] In contrast, mice lacking PAI-1 exhibit accelerated muscle regeneration. 7 Despite its robust effect on skeletal muscle regeneration, the molecular mechanisms by which the plasminogen system regulates this process remain largely undefined. Clearance of the provisional fibrin matrix that is deposited after muscle injury may be one mechanism by which uPA promotes regeneration. 8 However, uPA may also promote tissue repair through other pathways, such as the proteolytic activation of growth factors, including hepatocyte growth factor (HGF). HGF is synthesized and secreted as an inactive single-chain molecule, and proteolytic cleavage results in formation of the active 2-chain form, which has affinity for the c-met receptor. [10][11][12] uPA is one of a select group of proteases known to activate HGF, 11,12 the others being tissue-type plasminogen activator, factor XIa, factor XIIa, matriptase, and HGF activator. [13][14][15] In addition, uPA app...

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Section: Org Fromsupporting

confidence: 91%

Urokinase-type plasminogen activator increases hepatocyte growth factor activity required for skeletal muscle regeneration

Sisson

Nguyen

et al. 2009

Blood

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“…tPA enhances cell proliferation in a variety of cellular systems, 1,[62][63][64][65][66] including pancreatic cancer, 38 -40 although the molecular mechanism underlying this effect has not been well characterized. Maupas-Schwalm et al 1 reported that the mitogenic effects of tPA on smooth muscle cells require the activation of Src and ERK1/2 and are independent from its catalytic activity.…”

Section: Discussionmentioning

confidence: 99%

“…tPA catalytic-independent activation of the ERK1/2 pathway and subsequent cell proliferation induction is important for understanding the role of this protease in pancreatic cancer progression. Indeed, the effects of tPA seem to be context-dependent; in human fibroblasts and endothelial cells, proteolytic activity is not required for proliferation, 1,62,63 whereas in vascular smooth muscle cells, 66 mouse fibroblasts, 65 and hepatocytes, 64 proteolytic activity is required for this event. The complexity of signaling by tPA is also underlined by the finding that, in fibroblasts, tPA induces matrix metalloproteinase-9 gene expression in a non-catalytic manner through the activation of the ERK1/2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and Annexin A2

Ortiz-Zapater

Peiró

Roda

et al. 2007

The American Journal of Pathology

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Tissue plasminogen activator (tPA) is overexpressed in pancreatic ductal carcinoma and is involved in tumor progression. This effect is probably mediated through the activation of angiogenesis, cell invasion, and cell proliferation. Previous studies support the notion that the effects of tPA on cell invasion require its proteolytic activity. Here, we report the molecular mechanism responsible for the proliferative effects of tPA on pancreatic tumor cells. tPA activates the extracellular signal-regulated kinase 1/2 signaling pathway in a manner that is independent of its catalytic activity. We also show that at least two membrane receptors, epidermal growth factor receptor and annexin A2, which are overexpressed in pancreatic cancer, are involved in the transduction of tPA signaling in pancreatic tumors. This observation suggests the establishment of an amplification loop in tumor cell proliferation. Double immunofluorescence experiments showed co-localization of tPA/epidermal growth factor receptor and tPA/annexin A2 in pancreas cancer cells. These results add novel insights into the non-catalytic functions of tPA in cancer and the molecular mechanisms behind the effects of this protease on cell proliferation, including a role for epidermal growth factor receptor. (Am J Pathol 2007, 170

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“…In particular we are interested in verifying the possible role of phosphorylation in relationship with their PG-independent enzymatic activities [10, 33,34] and mitogenic effect exerted on human fibroblasts [35], also considering the interaction with PA receptors and inhibitors.…”

Section: Immunological Recognition Of P-ser and P-thr Residues In T-pmentioning

confidence: 99%

Phosphorylation of human plasminogen activators and plasminogen

et al. 1995

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Plasminogen (PC), urokinase-type plasminogen activator (u-PA) and tissue-type PA (t-PA) are the main molecules involved in fibrinolysis and in many other physiological and pathological processes. In the present study we report that human t-PA, purified from human melanoma cells, and PG, purified from human plasma, both contain P-Tyr residues, as revealed by immunoblotting analyses with monoclonal anti-P-Tyr antibodies. In addition HPLC amino acid analysis of acid-hydrolyzed t-PA, PG and u-PA, shows that: (i) P-Ser and P-Tyr residues are present in t-PA; (ii) P-Thr and P-Tyr are present in PG; (iii) P-Ser, P-Thr and P-Tyr are present in u-PA. The utilization of monoclonal anti-P-Ser and anti-P-Thr antibodies in immunoblotting experiments has confirmed these data which indicate that phosphorylation is a common feature of PAS and of PG.

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Urokinase-Type and Tissue-Type Plasminogen Activators as Growth Factors of Human Fibroblasts

Cited by 77 publications

References 0 publications

Urokinase-type plasminogen activator increases hepatocyte growth factor activity required for skeletal muscle regeneration

Urokinase-type plasminogen activator increases hepatocyte growth factor activity required for skeletal muscle regeneration

Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and Annexin A2

Phosphorylation of human plasminogen activators and plasminogen

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