NDR kinases regulate essential cell processes from yeast to humans

The NDR (nuclear Dbf2-related) kinase family is conserved from yeast to humans, and is a subgroup of the serine/threonine AGC kinases. NDR kinases have important roles during mitotic progression, cytokinesis, morphological changes, cell proliferation and apoptosis.The yeast NDR kinases, Dbf2p, Cbk1p, Sid2p and Orb6p, are functionally the best characterized members. They are essential components of signalling networks that control either morphological changes or mitotic exit.In flies, large tumour suppressor (Lats; one out of the two Drosophila melanogaster NDR relatives) is a central component of the Hippo pathway, and regulates tissue growth. A similar pathway that controls cell proliferation and death might also exist in humans, but still needs to be verified experimentally.NDR kinases are also important for dendritic/neurite outgrowth. Trc (tricornered) and SAX-1 (sensory axon guidance-1) (NDR kinases in D. melanogaster and Caenorhabditis elegans, respectively) are required for correct dendritic tiling.The regulation of NDR kinases at the molecular level is best understood for the mammalian kinases NDR1 and NDR2. Autophosphorylation on Ser281 (activation segment) and phosphorylation on Thr444 (hydrophobic motif) of NDR1 by MST3 (a STE20-like kinase) is essential for kinase activation.Interaction with its co-activator MOB (Msp1-one binder) through a conserved N-terminal domain is also an important step in the activation process of NDR kinases.Members of the NDR protein-kinase family consist of an N-terminal domain (NTR, N-terminal regulatory domain), and have an insertion in their kinase domain between subdomains VII and VIII, therefore preceding the activation segment.Two out of four mammalian NDR kinases, LATS1 and LATS2, function as tumour suppressors, whereas the other two members, NDR1 and NDR2, are probably proto-oncogenes.Unravelling how LATS1/2 and NDR1/2 contribute to cellular transformation and consequently, the development of cancer, is an important challenge for the future.