Dbf2-activated nuclear (NDR) family members are highly conserved serine/threonine protein kinases that work in concert with the Hippo signaling pathway and play a key role in regulating the proliferation and survival of non-neuronal cells. Recent studies using a variety of animal models have shown that NDR kinases are regulators of many aspects of neuron development after mitosis, including progenitor cell proliferation, fate norms, and circuit formation, all of which are essential for neuronal function.
NDR family kinases and signal transduction
NDR kinase is a major regulator of cell proliferation and apoptosis. However, in neurons, these enzymes appear to play a broader role, including neural fate specification, neurite outgrowth/branch determination, and receptive field determination. Some recent excellent reviews have discussed signal transduction pathways involved in NDR activity, cellular processes regulated by NDR kinases, and proteins that interact with these kinases. Genetic studies of Ndr kinases in yeast and invertebrates have determined that Ndr family kinases play an evolutionarily conservative role in cell morphogenesis, presumably by controlling Rho GTPase signaling. At the same time, pathological studies of the human Ndr kinases Ndr1 and Ndr2 have revealed a potential relationship between these factors and tumor development. For example, human Ndr1 has been found to be upregulated in progressive ductal carcinoma and certain melanoma cell lines. Similarly, Ndr2 levels are elevated in metastatic lung cancer cell lines. These observations suggest that Ndr kinases may have protocancer activity. On the other hand, recent studies have also shown that mammals Ndr1 and Ndr2 mediate apoptosis downstream of the tumor suppressor MST kinase and RASSFs. Consistently, a recent report showed that Ndr1 knockout mice are susceptible to T-cell lymphoma. Therefore, Ndr kinases appear to regulate cell growth and apoptosis, although the exact underlying mechanism has not been identified.
Functions
Like most AGC kinases, NDR kinase subclasses are activated by phosphorylation of serine or threonine that is conserved in the activation region at the C-terminus of the kinase catalytic domain. NDR kinases are characterized by the indispensable binding of the surface functions of MOB coactivators, and MOB coactivators are also widely present in eukaryotes. Most NDR kinase catalytic domains also contain an extended insertion region that can serve as a self-inhibitory element. The NDR kinase family can be further divided into two subgroups, namely the Ndr family and the Wts / Lats family. Humans have four types of NDR kinases: Ndr1 (or STK38), Ndr2 (or STK38L), Lats1 (large tumor suppressor factor-1), and Lats2. In animals, these kinases have been reported to play a role in the regulation of multiple processes, including cell proliferation control, proto-oncoprotein activity, apoptosis, centrosome replication, and tissues of neuronal dendrites. In single-cell eukaryotes, Ndr kinases play an important role in controlling cell cycle and morphogenesis. In fission yeast Schizosaccharomyces cerevisiae, an organism suitable for studying cell morphogenesis, the Ndr kinase Orb6 plays a part in the control of cell polarity and morphogenesis through the regulation of small Rho-type GTPase Cdc42. Specifically, Orb6 kinase spatially restricts Cdc42 activation to the polarized ends of the cell, resulting in Cdc42-dependent formins For3 (F-actin cable polymerization factor) being activated at the cell end as well, thereby ensuring proper cell growth and polarization. After the loss of Orb6 kinase function, cells will not be able to maintain a polarized cell shape and become rounded.
Neurite growth and branching
Ndr kinases regulate the growth and branching of neurites during the formation of circuits in the invertebrate and vertebrate nervous systems. In an earlier study, Stork et al. Screen for genes induced in mouse amygdala during fear memory consolidation, and isolate Ndr2 as a potential candidate gene. Since the overexpression of Ndr2 promotes the growth of neurites in rat PC12 cells and mouse primary cultured neurons, they proposed that it may play a role in neurite remodeling during fear memory consolidation. In Drosophila and C. elegans sensory neurons, Ndr kinases are required for dendritic branches. In these cases, Ndr kinase may promote neurite growth / branch through Rho family GTPase-dependent cytoskeleton remodeling in neurites.
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