The human body consists of an estimated 100 trillion cells. In order to function as one single unit, cells exchange and process enormous amounts of information. Biologists have termed this flow of information “signalling”. Defects in signalling can lead to grave diseases such as diabetes and cancer. A particular class of proteins, so-called protein kinases, play a key role in relaying and amplifying signals within each cell. My laboratory has identified the mammalian NDR protein kinases which are conserved from yeast to man. The Hippo signalling pathway is currently receiving much attention in the context of development and cancer. However, although the Hippo kinase in fly and its homologs MST1 and MST2 in mammals activate both LATS and NDR kinases, the NDR branch of the pathway is rarely taken into consideration. Several reports describe deregulated Ndr levels in human cancers, but the functional relevance of the expression changes remains unknown. Therefore, there is a pertinent need to comprehensively address the in vivo roles of NDR kinases in mammalian development and cancer.
We have previously characterized how the activity of NDR kinases is regulated in mammalian cells. Importantly, we could subsequently show that old mice which lack NDR1 – one of the two forms of the kinase that exist in mammals – develop T-cell lymphoma, a cancer of the immune system. Moreover, we found that both NDR isoforms can compensate for each other. To further study the role of NDR kinases in mammalian development and disease, we have therefore generated a mouse line which allows us to remove both NDR1 and NDR2. Mice which lack both NDR isoforms die as embryos, showing that NDR kinases are essential for mammalian development. Using this mouse line we will pursue initial evidence that NDR kinases might regulate embryonic growth via controlling c-myc and p21 levels, two proteins which play key roles in cellular multiplication (proliferation). Moreover, we will investigate the putative link between NDR kinases and the Notch pathway, an important player in cellular differentiation. Given that loss of NDR kinases predisposes mice to T-cell lymphoma, we have designed a mouse model which allows us to specifically study the role of NDR kinases in T-cell biology. While NDR1 levels are particularly high in organs of the immune system, the second isoform, NDR2 is strongly expressed in the colon. As NDR1 appears to protect against T-cell lymphoma, we hypothesize that NDR2 might function as a tumour suppressor in the colon. To address this hypothesis, we have generated a mouse line where we can eliminate both NDR1 and NDR2 from the colonic epithelium, the tissue in which colon cancer arises. In parallel, we will extend our studies to human colon cancer cell lines asking whether NDR kinases are important for their cancerous nature. Finally, we will screen human colon cancer samples to assess whether our findings are relevant to human colon cancer patients.
In summary, we are convinced that the presented project will complement our knowledge about the Hippo pathway in general and the contributions of NDR kinases to normal mammalian development and cancer in particular.