Abstract
ABSTRACTThe MARK/PAR-1 family of kinases are conserved regulators of cell polarity that share a conserved C-terminal kinase-associated domain (KA1). Localization of MARK/PAR-1 kinases to specific regions of the cell cortex is a hallmark of polarized cells. In Caenorhabditis elegans zygotes, PAR-1 localizes to the posterior cortex under the influence of another polarity kinase, aPKC/PKC-3. Here, we report that asymmetric localization of PAR-1 protein is not essential, and that PAR-1 kinase activity is regulated spatially. We find that, as in human MARK1, the PAR-1 KA1 domain is an auto-inhibitory domain that suppresses kinase activity. Auto-inhibition by the KA1 domain functions in parallel with phosphorylation by PKC-3 to suppress PAR-1 activity in the anterior cytoplasm. The KA1 domain also plays an additional role that is essential for germ plasm maintenance and fertility. Our findings suggest that modular regulation of kinase activity by redundant inhibitory inputs contributes to robust symmetry breaking by MARK/PAR-1 kinases in diverse cell types.
Highlights
Cell polarity is central to many cellular and developmental processes, such as axon specification, cell migration, tissue morphogenesis and asymmetric cell division
Asymmetric localization of PAR-1 at the cell cortex is a prominent characteristic of polarized cells, studies in C. elegans have suggested that cortical localization is not essential for PAR-1 function (Boyd et al, 1996) and that asymmetric PAR-1 activity in the cytoplasm is crucial for zygote polarity (Griffin et al, 2011)
We found that inactivation of PAR-2 by RNA-mediated interference (RNAi) did not prevent P granule asymmetry (Fig. 7B,C), which is consistent with previous reports that PAR-2 is not essential for polarization of PAR-1 activity (Boyd et al, 1996; Griffin et al, 2011; Ramanujam et al, 2018)
Summary
Cell polarity is central to many cellular and developmental processes, such as axon specification, cell migration, tissue morphogenesis and asymmetric cell division. The kinase PAR-1 is a conserved regulator of cell polarity in eukaryotes. PAR-1 often localizes to specific membrane domains. In Drosophila oocytes and Caenorhabditis elegans zygotes, PAR-1 localizes to the posterior cell cortex, and this asymmetry is essential to concentrate germ cell fate determinants to the posterior end of the embryo at which the germline will form (Goldstein and Macara, 2007; Guo and Kemphues, 1995; Shulman et al, 2000; Tomancak et al, 2000; Wu and Griffin, 2017). The mechanisms that regulate PAR-1 activity in space are central to the polarization process, but are still poorly understood. Asymmetric localization of PAR-1 at the cell cortex is a prominent characteristic of polarized cells, studies in C. elegans have suggested that cortical localization is not essential for PAR-1 function (Boyd et al, 1996) and that asymmetric PAR-1 activity in the cytoplasm is crucial for zygote polarity (Griffin et al, 2011)
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