Lasse Holt-Danborg

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The main focus of my PhD is to investigate the highly oncogenic protease matriptase. Matriptase is a membrane anchored serine protease, which is expressed in most epithelial tissues in the body. Studies in transgenic mice have shown that a slight overexpression of matriptase singlehandedly can induce cancer. Therefore, the general hypothesis within the field is that dysregulated matriptase activity is highly oncogenic. Prostasin, which is another membrane-anchored serine protease, is activated by matriptase, and prostasin also cleaves matriptase in what has been described as a reciprocal zymogen activation complex. Whether the cleavage of matriptase by prostasin is activating however remains elusive. Both matriptase and prostasin are regulated by the two serine protease inhibitors, HAI-1 and HAI-2.

Our studies are focusing on how the proteolytic activity of matriptase and prostasin is regulated due to its oncogenic potential.

We have identified two inhibitors which inhibit the autoactivation of matriptase. Furthermore, we have investigated how the regulatory proteolytic function of prostasin affects matriptase activity.  At the moment the understanding of the biological function of the matriptase/prostasin-HAI-1/HAI-2 system is limited. We have therefore investigated mutations in the gene encoding matriptase giving rise to ichthyosis also known as fish skin and mutations in HAI-2 causing debilitating sodium diarrhea in children. Furthermore, we have developed matriptase inhibitory antibodies that can be used to specifically measure matriptase activity or inhibit matriptase activity in a clinical setting.

We hope that the matriptase field will contribute with a new understanding of the mechanisms underlying epithelial cancers that will prove useful in diagnosis and/or treatment