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The role of tumor suppressor proteins in the development of
malignancy has made the understanding of their molecular mechanisms of
action of great importance. Maspin is a tumor suppressor produced by a
number of cell types of epithelial origin. Exogenous recombinant maspin
has been shown to block the growth, motility, and invasiveness of
breast tumor cell lines in vitro and in vivo.
Although belonging to the the serine proteinase inhibitor (serpin)
superfamily of proteins, the molecular mechanism of maspin is currently
unknown. Here we show that the reactive site loop of maspin exists in
an exposed conformation that does not require activation by cofactors.
The reactive site loop of maspin, however, does not act as an inhibitor
of proteinases such as chymotrypsin, elastase, plasmin, thrombin, and
trypsin but rather as a substrate. Maspin is also unable to inhibit
tissue and urokinase type plasminogen activators. Stability studies
show that maspin cannot undergo the stressed-relaxed transition typical
of proteinase-inhibitory serpins, and the protein is capable of
spontaneous polymerization induced by changes in pH. It is likely,
therefore, that maspin is structurally more closely related to
ovalbumin and angiotensinogen, and its tumor suppressor activity is
independent of a latent or intrinsic trypsin-like serine
proteinase-inhibitory activity.
Volume 270,
Number 26,
Issue of June 30, pp. 15832-15837, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
EVIDENCE THAT MASPIN IS NOT A PROTEASE INHIBITORY SERPIN
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