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  • br Conflict of interests br Acknowledgements This

    2021-11-26


    Conflict of interests
    Acknowledgements This work was supported by the National Institutes of Health grants HD058577 and ES01678 to Kirill Kiselyov. We thank Sreeram Ravi for technical support. We also thank Mike Myers at the University of Pittsburgh Cancer Institute Flow Cytometry Facility.
    Introduction The ability to establish, maintain, and alter polarity is central to the function of nearly all eukaryotic cell CNQX types (Campanale et al., 2017, Mayor and Etienne-Manneville, 2016, Rodriguez-Boulan and Macara, 2014, Schelski and Bradke, 2017, St Johnston and Ahringer, 2010). Dysregulation of cell polarity is associated with multiple pathologies, including tumorigenesis and neurodegenerative disease (Martin-Belmonte and Perez-Moreno, 2011, Millecamps and Julien, 2013). NDR/LATS kinases are members of a subfamily of the AGC serine-threonine kinases and are important for polarized cellular differentiation in multiple systems (Hergovich et al., 2006). NDR/LATS kinases such as Trc (Drosophila), NDR1 and NDR2 (NDR1/2) (mammals), and SAX-1/SAX-2 (C. elegans) share evolutionarily conserved functions in coordinating neurite branching and patterning of neuronal fields (Hergovich, 2016). Other NDR/LATS kinases such as Wts (Drosophila), LATS1 and LATS2 (LATS1/2) (mammals) and WTS-1 (C. elegans) regulate polarized differentiation of epithelia and other cell types (Furth and Aylon, 2017). In budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe, NDR/LATS kinases Cbk1 and Orb6, respectively, are required for polarized cellular morphogenesis (Bidlingmaier et al., 2001, Racki et al., 2000, Verde et al., 1998). Other essential biological processes regulated by NDR/LATS kinases include centrosome duplication, cell-cycle progression, autophagy, and apoptosis (Hergovich, 2016). Identification of targets of NDR/LATS kinases is crucial for understanding how they CNQX regulate complex biological processes. To date, surprisingly few targets of NDR/LATS kinases are known (Hergovich, 2013). The best characterized targets in mammals and Drosophila are the transcriptional co-activators YAP and TAZ (targets of LATS1/2) and Yki (target of Wts), respectively (Yu and Guan, 2013). Phosphorylation of YAP, TAZ, and Yki is an important element of the Hippo pathway, a tumor suppressor pathway regulating cell shape and proliferation (Hansen et al., 2015). In addition, NDR1/2 phosphorylate p21 cyclin-dependent kinase inhibitor and MYPT1 phosphatase, which regulate the G1/S transition and G2 DNA damage checkpoint, respectively (Chiyoda et al., 2012, Cornils et al., 2011). In neurons, NDR1/2 phosphorylate AP2-associated kinase 1 (AAK1) and Rabin8, the guanine nucleotide exchange factor (GEF) for Rab8 guanosine triphosphatase (GTPase), which are involved in vesicle trafficking and are important for dendrite growth regulation and dendritic spine development, respectively (Ultanir et al., 2012). In budding yeast, Cbk1 inactivation or inhibition affects both cell morphogenesis and asymmetry of gene expression between mother and daughter cell. Cbk1 phosphorylates the transcription factor Ace2 and the RNA-binding protein Ssd1, a translational regulator (Weiss, 2012). Cbk1 is also reported to phosphorylate Sec2, a GEF for the Rab GTPase Sec4 (Kurischko et al., 2008). In fission yeast, temperature-sensitive orb6-25 mutants lose polarity at non-permissive temperature, and cells become round rather than rod shaped (Verde et al., 1998). In vitro, Orb6 can phosphorylate the Ssd1 homolog Sts5 (Nuñez et al., 2016), as well as Gef1, a GEF for the Rho-family cell-polarity GTPase Cdc42 (Das et al., 2015). Phosphorylation of Gef1 serine-112 is thought to promote Gef1 association with 14-3-3 protein Rad24, restricting Gef1’s ability to activate Cdc42 (Das et al., 2015). Accordingly, Orb6 inactivation leads to ectopic localization of active Cdc42 (Cdc42-GTP) on cell sides, with subsequent recruitment of formin For3 to these ectopic sites (Das et al., 2009). These events have been proposed to drive reorganization of actin cable nucleation and redirection of intracellular transport, leading to increased cell width in Orb6-inhibited cells (Das et al., 2009).