Maspin inhibits cell migration in the absence of protease inhibitory activity.
Maspin is a member of the serpin family of protease inhibitors and is a tumor suppressor gene acting at the level of tumor invasion and metastasis. This in vivo activity correlates with the ability of maspin to inhibit cell migration in vitro. This behavior suggests that maspin inhibits matrix-degrading proteases, such as those of the plasminogen activation system, in a similar manner to the serpin PAI-1. However, there is controversy concerning the protease inhibitory activity of maspin. It is devoid of activity against a wide range of proteases, in common with other non-inhibitory serpins, but has recently been reported to inhibit plasminogen activators associated with cells and other biological surfaces (Sheng, S. J., Truong, B., Fredrickson, D., Wu, R. L., Pardee, A. B., and Sager, R. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 499-504; McGowen, R., Biliran, H., Jr., Sager, R., and Sheng, S. (2000) Cancer Res. 60, 4771-4778). We have compared the effects of maspin with those of PAI-1 in a range of situations in which plasminogen activation is potentiated, reflecting the biological context of this proteolytic system: urokinase-type plasminogen activator bound to its receptor on the surface of tumor cells, tissue-type plasminogen activator specifically bound to vascular smooth muscle cells, fibrin, and the prion protein. Maspin was found to have no inhibitory effect in any of these situations, in contrast to the efficient inhibition observed with PAI-1, but nevertheless maspin inhibited the migration of both tumor and vascular smooth muscle cells. We conclude that maspin is a non-inhibitory serpin and that protease inhibition does not account for its activity as a tumor suppressor.
Bass
Rosemary
R
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom.
Fernández
Ana-María Moreno
AM
Ellis
Vincent
V
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D002384:Catalysis; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000166:cytology; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015843:Serpins / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017395:Plasminogen Activator Inhibitor 1; D011506:Proteins; D011994:Recombinant Proteins; C085344:SERPIN-B5; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D010958:Plasminogen; D010959:Tissue Plasminogen Activator