Maspin Inhibits Cell Migration in the Absence of Protease Inhibitory Activity

Abstract

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 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 noninhibitory serpin and that protease inhibition does not account for its activity as a tumor suppressor.

G-helix of Maspin Mediates Effects on Cell Migration and Adhesion

“…This is in good agreement with previous studies identifying interactions between maspin and ␤1 integrins (19,20); we showed that maspin binds to integrins ␣3␤1 and ␣5␤1 on the surface of VSMCs, but not ␣v␤3, which is also abundant on the surface of these cells (20). We observed a rapid inhibition of cell migration by maspin and also a dynamic regulation of the activation state of integrins (9,20), rather than a change in integrin expression. The findings presented here indicate that the G-helix of maspin is also reliant on the presence of active ␤1 on the cell surface for its action, as the peptide fails to influence cell migration when ␤1 is functionally blocked.…”

“…However, the mechanism of action of maspin remains largely unresolved. Although early evidence suggested that maspin was an inhibitory serpin able to block plasminogen activation by urokinase plasminogen activator and tissue-type plasminogen activator (11)(12)(13), we demonstrated that this was not the case in a number of conditions where the serpin PAI-1 was inhibitory (9). That maspin is a noninhibitory serpin is supported by crystal structure data revealing that its RCL does not correspond with those found in inhibitory serpins (14,15).…”

“…It inhibits angiogenesis in vivo (7) and causes apoptosis when expressed in endothelial cells (8). In addition, we have shown that maspin can inhibit the migration of vascular smooth muscle cells (VSMCs) 3 (9), which has potential ramifications for conditions resulting from vascular injury such as atherosclerosis.…”

Maspin – the most commonly-expressed gene of the 18q21.3 serpin cluster in lung cancer – is strongly expressed in preneoplastic bronchial lesions

“…While the 42 kDa maspin protein shows extensive homology to other serpins (Potempa et al, 1994), a clear inhibitory role has yet to be demonstrated. Functional investigations, based on various model systems, have consistently suggested that expression of the 42 kDa protein is linked to a reduced ability of cells to move, invade or metastasize (Shi et al, 2001;Bass et al, 2002;Abraham et al, 2003). Further supporting the tumour suppressor argument, it has been suggested that maspin expression may be directly induced by p53 (Zou et al, 2000).…”

Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis

“…In human primary PCs, maspin expression consistently appears to be down-regulated at the critical transition from noninvasive, low-grade disease to highly invasive, high-grade PC (34). Although the proteolytic inhibitory activity of maspin has been a subject of debate (32,35,36), probably because of the variations of the in vitro experimental systems, we have shown that maspin exerts a potent inhibitory effect on PC cells DU145-associated uPA͞uPAR (uPA receptor) (32,36). The proteolytic inhibitory activity of maspin correlates with its effect in inhibiting PC cell motility and invasion in vitro (32,36).…”