Molecular and Cellular Biology of Plasminogen Activation

i024i
Matriptase Is an Essential Inhibitory Target for
Hepatocyte Growth Factor Activator Inhibitor-1 during
both Embryonic Development and Postnatal Life
Szabo R*, Molinolo A, List K, Bugge TH
Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, Maryland, USA
Presenting author e-mail: rszabo@nidcr.nih.gov
Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a Kunitz-type transmembrane serine
protease inhibitor proposed to inhibit the activity of several trypsin-like serine proteases,
including hepsin, hepatocyte growth factor activator, prostasin (CAP1/PRSS8), and matriptase.
Here we generated HAI-1-deficient mice to determine the biological function of HAI-1 and
identify physiological HAI-1 inhibitory targets during development and postnatal life. HAI-
1-deficient mice died at mid-gestation due to placental insufficiency caused by a disruption of
the epithelial integrity of placental chorionic trophoblasts associated with chorionic basement
membrane dissolution, loss of E-cadherin, and loss of membrane-associated b-catenin.
Interestingly, however, matriptase gene ablation in HAI-1-deficient embryos restored the integrity
of chorionic trophoblasts and enabled both normal placentation and development to term. HAI-
1 was recently reported to also be required for mouse postnatal survival beyond two weeks. To
determine the inhibitory targets for HAI-1 during postnatal life, we generated HAI-1 null mice
in a matriptase hypomorphic background, which display 82 - >99 % reduction in matriptase
mRNA levels in epithelial tissues. Low matriptase levels enabled both embryonic development
and normal postnatal survival of HAI-1-deficient mice when followed for up to six months. Taken
together, this study identifies matriptase as an essential inhibitory target for HAI-1 during both
embryonic development and postnatal life.
36 X I t h I n t e r n a t i o n a l W o r k s h o p o n