Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA.
Hepatocyte growth factor, also known as scatter factor, is a complete mitogen for hepatocytes that bears sequence and structural homology with plasminogen. Because it exists in both a mitogenically inactive single-chain form and an active two-chain form, we were interested in determining whether plasminogen activators could properly cleave single-chain hepatocyte growth factor to generate active two-chain hepatocyte growth factor. Herein we report that both urokinase-type plasminogen activator and tissue-type plasminogen activator can cleave single-chain hepatocyte growth factor, generating two-chain hepatocyte growth factor. When equal quantities of plasminogen activator-treated and activator-untreated hepatocyte growth factor are compared in serum-free in vitro bioassays, the treated hepatocyte growth factor is mitotically more active. Also, urokinase-type plasminogen activator was inactive against hepatocyte growth factor molecules with a mutated cleavage site. This suggests that urokinase-type and tissue-type plasminogen activator may be natural biological regulators of hepatocyte growth factor. Because the active form of hepatocyte growth factor is a powerful stimulator of DNA synthesis and cell motility, these findings may be relevant in understanding the role of plasminogen activators in the biology of cancer invasion and metastasis.
Mars
W M
WM
Department of Pathology, University of Pittsburgh, Pennsylvania 15261.
Zarnegar
R
R
Michalopoulos
G K
GK
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005341:Fibrinolysin / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013300:Streptokinase / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D017228:Hepatocyte Growth Factor; D004247:DNA; D013300:Streptokinase; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator