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Investigating the in vivo roles of mammalian NDR kinases in development and colon cancer

English title Investigating the in vivo roles of mammalian NDR kinases in development and colon cancer
Applicant Hemmings Brian
Number 138287
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.12.2011 - 28.02.2015
Approved amount 354'000.00
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Keywords (7)

NDR; Hippo; development; cancer; p21; c-myc; Notch

Lay Summary (English)

Lead
Lay summary

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.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
NDR Functions as a Physiological YAP1 Kinase in the Intestinal Epithelium
Zhang Lei, Tang Fengyuan, Terracciano Luigi, Hynx Debby, Kohler Reto, Bichet Sandrine, Hess Daniel, Cron Peter, Hemmings Brian, Hergovich Alexander, Schmitz-Rohmer Debora (2015), NDR Functions as a Physiological YAP1 Kinase in the Intestinal Epithelium, in Current Biology, 25(3), 296-305.
NDR Kinases Are Essential for Somitogenesis and Cardiac Looping during Mouse Embryonic Development
Schmitz-Rohmer Debora (2015), NDR Kinases Are Essential for Somitogenesis and Cardiac Looping during Mouse Embryonic Development, in Plos one, 1-21.
The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility
Tang Fengyuan (2015), The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility, in Science Signaling, 8(397), ra100-ra100.
hMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiforme
Tang Fengyuan, Zhang Lei, Xue Gongda, Hynx Debby, Wang Yuhua, Cron Peter D., Hundsrucker Christian, Hergovich Alexander, Frank Stephan, Hemmings Brian A., Schmitz-Rohmer Debora (2014), hMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiforme, in Cancer Research, 74(14), 3779-3789.

Associated projects

Number Title Start Funding scheme
130838 Regulation of epithelial-mesenchymal transition and metastasis through phosphorylation of the transcription factor Twist by protein kinase B (PKB/Akt) 01.07.2010 Project funding (Div. I-III)

Abstract

NDR kinases are highly conserved from yeast to man. Loss-of-function models of Ndr homologs in yeast and flydemonstrate essential functions of the respective kinases (reviewed in (6)). Mammalian Ndr1 and Ndr2 are widelyexpressed (17). The Hippo pathway is currently receiving much attention in the context of development andcancer (97). However, although the STE-20 kinase Hippo in fly and its homologs MST1 and MST2 in mammalsactivate both LATS and NDR kinases, the NDR branch of the pathway is rarely considered. Several reportsdescribe deregulated Ndr transcript levels in human cancers but the functional relevance of the expressionchanges remains to be addressed (reviewed in (33)). Therefore, there is a pertinent need to comprehensivelyaddress the in vivo roles of NDR kinases in mammalian development and cancer.To comprehensively address this issue, we have generated the complete Ndr1/2 double knock-out mouseline as well as two tissue-specific derivatives thereof (unpublished). Complete loss of Ndr1/2 results in embryoniclethality at mid-gestation, indicating that mammalian NDR kinases serve essential functions in embryonicdevelopment. Based on our previously published (21) and additional unpublished recent data, we hypothesizethat NDR kinases control embryonic growth via c-myc stabilization and repression of p21. We will use Ndr-nullembryos and NDR-deficient mouse embryonic fibroblasts to test this hypothesis. Moreover, we will follow up initialobservations that point towards a potential role of NDR kinases as up-stream regulators of Notch signaling viadirect phosphorylation of the Notch intra-cellular domain (NICD).We previously reported that loss of Ndr1 predisposes mice to T-cell lymphoma (30). Furthermore, theNDR up-stream kinase MST1 was shown to play an important role in T-cell proliferation and survival as well asegress from the thymus, trafficking and homing (82-87, 89). Therefore, we have generated a T-cell specific Ndr1/2double KO mouse line to investigate whether NDR kinases serve as down-stream effectors of MST-signaling in Tcelldevelopment and function. Notch signaling plays a pivotal role at different steps T-cell differentiation andfunction (90). Hence NDR kinases might represent a mechanistic link between MST kinases and the Notchpathway, a hypothesis which we will evaluate if we can establish the NICD as an in vivo target of NDR kinases.We recently showed that NDR kinases possess tumor suppressive properties in the context of T-celllymphoma (30). NDR2 protein levels are particularly high in the colon. Therefore, we have generated anintestinal-epithelial Ndr1/2 double-KO mouse line to investigate whether NDR kinases exert tumor suppressivefunctions in the context of colon cancer. Preliminary data indicate that these mice are indeed more susceptible toAzoxymethane-induced colonic nodule formation. Once we have confirmed this initial observation, we will extendour studies to human colon cancer cell lines asking whether NDR kinases are important for their cancerousphenotype both in tissue culture and upon injection into nude mice. Finally, we will screen human colon cancersamples to assess whether our findings in the mouse are relevant to human colon cancer patients.In summary, we are convinced that the present proposal has strong potential to complement ourknowledge about the Hippo pathway in general and the contributions of NDR kinases in particular.
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