Activation of Hepatocyte Growth Factor by the Plasminogen Activators UPA and TPA

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 1993 Sep 1

PMID 8362987

Citations 110

Authors

W M Mars

R Zarnegar

G K Michalopoulos

Affiliations

Soon will be listed here.

Abstract

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.

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References

Ellis V, Behrendt N, Dano K . Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. J Biol Chem. 1991; 266(19):12752-8. View

Testa J, Quigley J . The role of urokinase-type plasminogen activator in aggressive tumor cell behavior. Cancer Metastasis Rev. 1990; 9(4):353-67. DOI: 10.1007/BF00049524. View

Bieche I, Champeme M, Matifas F, Hacene K, Callahan R, Lidereau R . Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer. Lancet. 1992; 339(8786):139-43. DOI: 10.1016/0140-6736(92)90208-k. View

Hernandez J, Zarnegar R, Michalopoulos G . Characterization of the effects of human placental HGF on rat hepatocytes. J Cell Physiol. 1992; 150(1):116-21. DOI: 10.1002/jcp.1041500116. View

Lokker N, Mark M, Luis E, Bennett G, Robbins K, Baker J . Structure-function analysis of hepatocyte growth factor: identification of variants that lack mitogenic activity yet retain high affinity receptor binding. EMBO J. 1992; 11(7):2503-10. PMC: 556725. DOI: 10.1002/j.1460-2075.1992.tb05315.x. View

Hoyer-Hansen G, Ronne E, Solberg H, Behrendt N, Ploug M, Lund L . Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem. 1992; 267(25):18224-9. View

Gak E, Taylor W, Chan A, Rubin J . Processing of hepatocyte growth factor to the heterodimeric form is required for biological activity. FEBS Lett. 1992; 311(1):17-21. DOI: 10.1016/0014-5793(92)81356-q. View

Naka D, Ishii T, Yoshiyama Y, Miyazawa K, Hara H, Hishida T . Activation of hepatocyte growth factor by proteolytic conversion of a single chain form to a heterodimer. J Biol Chem. 1992; 267(28):20114-9. View

Pepper M, Matsumoto K, Nakamura T, Orci L, Montesano R . Hepatocyte growth factor increases urokinase-type plasminogen activator (u-PA) and u-PA receptor expression in Madin-Darby canine kidney epithelial cells. J Biol Chem. 1992; 267(28):20493-6. View

10.

Jirtle R, Michalopoulos G, McLain J, Crowley J . Transplantation system for determining the clonogenic survival of parenchymal hepatocytes exposed to ionizing radiation. Cancer Res. 1981; 41(9 Pt 1):3512-8. View

11.

Collen D . On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb Haemost. 1980; 43(2):77-89. View

12.

Roche P, Campeau J, Shaw Jr S . Comparative electrophoretic analysis of human and porcine plasminogen activators in SDS-polyacrylamide gels containing plasminogen and casein. Biochim Biophys Acta. 1983; 745(1):82-9. DOI: 10.1016/0167-4838(83)90172-3. View

13.

RUSSELL W, McGowan J, BUCHER N . Partial characterization of a hepatocyte growth factor from rat platelets. J Cell Physiol. 1984; 119(2):183-92. DOI: 10.1002/jcp.1041190207. View

14.

Michalopoulos G, Houck K, Dolan M, Leutteke N . Control of hepatocyte replication by two serum factors. Cancer Res. 1984; 44(10):4414-9. View

15.

Nakamura T, Nawa K, Ichihara A . Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun. 1984; 122(3):1450-9. DOI: 10.1016/0006-291x(84)91253-1. View

16.

Stoker M, Gherardi E, Perryman M, Gray J . Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature. 1987; 327(6119):239-42. DOI: 10.1038/327239a0. View

17.

Ranby M, Brandstrom A . Biological control of tissue plasminogen activator-mediated fibrinolysis. Enzyme. 1988; 40(2-3):130-43. DOI: 10.1159/000469155. View

18.

Miyazawa K, Tsubouchi H, Naka D, Okigaki M, Arakaki N, Nakayama H . Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun. 1989; 163(2):967-73. DOI: 10.1016/0006-291x(89)92316-4. View

19.

Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A . Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989; 342(6248):440-3. DOI: 10.1038/342440a0. View

20.

Tashiro K, Hagiya M, Nishizawa T, Seki T, Shimonishi M, Shimizu S . Deduced primary structure of rat hepatocyte growth factor and expression of the mRNA in rat tissues. Proc Natl Acad Sci U S A. 1990; 87(8):3200-4. PMC: 53863. DOI: 10.1073/pnas.87.8.3200. View