Abstract
SummaryNDR/LATS kinases regulate multiple aspects of cell polarity and morphogenesis from yeast to mammals. Fission yeast NDR/LATS kinase Orb6 has been proposed to control cell polarity by regulating the Cdc42 guanine nucleotide exchange factor Gef1. Here, we show that Orb6 regulates polarity largely independently of Gef1 and that Orb6 positively regulates exocytosis. Through Orb6 inhibition in vivo and quantitative global phosphoproteomics, we identify Orb6 targets, including proteins involved in membrane trafficking. We confirm Sec3 and Sec5, conserved components of the exocyst complex, as substrates of Orb6 both in vivo and in vitro, and we show that Orb6 kinase activity is important for exocyst localization to cell tips and for exocyst activity during septum dissolution after cytokinesis. We further find that Orb6 phosphorylation of Sec3 contributes to exocyst function in concert with exocyst protein Exo70. We propose that Orb6 contributes to polarized growth by regulating membrane trafficking at multiple levels.
Highlights
The ability to establish, maintain, and alter polarity is central to the function of most eukaryotic cell types (Campanale et al, 2017; Mayor and Etienne-Manneville, 2016; Rodriguez-Boulan and Macara, 2014; Schelski and Bradke, 2017; St Johnston and Ahringer, 2010)
Through Orb6 inhibition in vivo and quantitative global phosphoproteomics, we identify Orb6 targets, including proteins involved in membrane trafficking
We confirm Sec3 and Sec5, conserved components of the exocyst complex, as substrates of Orb6 both in vivo and in vitro, and we show that Orb6 kinase activity is important for exocyst localization to cell tips and for exocyst activity during septum dissolution after cytokinesis
Summary
The ability to establish, maintain, and alter polarity is central to the function of most eukaryotic cell 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). Other essential biological processes regulated by NDR/LATS kinases include centrosome duplication, cell-cycle progression, autophagy, and apoptosis (Hergovich, 2016)
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