Functional characterization of mammalian NDR kinase deficiency : novel functions and insights into downstream signaling mechanisms

Protein kinases are important players in signal transduction. They are involved in the regulation of almost every aspect of biological regulation. Given their central role in signal transduction, aberrant protein kinase activities are involved in a variety of human diseases, such as diabetes or cancer. The human genome encodes for 518 protein kinases, which are further classified into groups, families and sub-families based on their catalytic domain. The NDR kinase family belongs to the AGC group (protein kinase A/G/C like) of serine/threonine kinases. Members of this family are highly conserved from yeast to men. Genetical and biochemical work on NDR kinases in yeast and invertebrates revealed, that NDR kinases are involved in the regulation of important biological processes such as mitotic exit, morphogenesis, neuronal and epithelial morphology, growth, proliferation and apoptosis amongst others. Although NDR kinases are implicated in a variety of biological processes amongst species, the topology of the signaling pathways regulating NDR kinases are remarkably conserved. NDR kinases from yeast to men are regulated by members of the Ste20 like kinases, MOB adaptor proteins and scaffolding proteins. The human genome encodes for 4 members of the NDR kinase family: NDR1, NDR2, LATS1 and LATS2. Although many of the biochemical mechanisms regulating NDR kinases have been worked out using human NDR1 and NDR2, functions for these two kinases have only been reported recently: Human NDR has been shown to function in centrosome duplication, the alignment of mitotic chromosomes and apoptosis signaling. Defects in regulation of these processes have been linked to tumor development. However, these functions were investigated using cell culture systems and physiological functions for NDR1 and NDR2 remain to be defined. Interestingly, NDR1 in these contexts has been shown to be regulated by components of the HIPPO tumor suppressor pathway. The tumor suppressor proteins Rassf1a, MST1/2 and hMOB1 have been shown to not only regulate NDR kinase activity, but also the activity of the other NDR family members LATS1 and LATS2. LATS kinases function as tumor suppressors by restricting the activity of the YAP oncogene. Given the interaction with known components of the HIPPO pathway, a tumor suppressive function for NDR1 and NDR2 seems possible. However, although first functions for human NDR kinases have been defined recently, signaling mechanisms downstream of NDR1 and NDR2 remain elusive. Addressing two of the major questions relating to mammalian NDR kinases, we define a first physiological function for NDR kinases in mice in tumor suppression. Deficiency and heterozygosity of NDR1 predisposes mice to T-cell lymphoma development. Reduction of NDR kinase expression results in increased resistance to pro-apoptotic stimuli. Furthermore we identify a novel role for NDR1 and NDR2 in the regulation of cell cycle progression. NDR1/2 directly regulate the protein stability of the proto-oncogene c-myc and the cyclin-dependent kinase inhibitor p21. Mammalian NDR kinases therefore seem to play important roles in tumor and cell biology by regulating proliferation and apoptosis.