Regulation of Cell Polarity by PAR-1/MARK Kinase

Abstract

PAR-1/MARK kinases are conserved serine/threonine kinases that are essential regulators of cell polarity. PAR-1/MARK kinases localize and function in opposition to the Anterior PAR proteins to control the asymmetric distribution of factors in a wide variety polarized cells. In this review, we discuss the mechanisms that control the localization and activity of PAR-1/MARK kinases, including their antagonistic interactions with the Anterior PAR proteins. We focus on the role PAR-1 plays in the asymmetric division of the C. elegans zygote, in the establishment of the anterior/posterior axis in the Drosophila oocyte and in the control of microtubule dynamics in mammalian neurons. In addition to conserved aspects of PAR-1 biology, we highlight the unique ways in which PAR-1 acts in these distinct cell types to orchestrate their polarization. Finally, we review the connections between disruptions in PAR-1/MARK function and Alzheimer’s disease and cancer.

The role of microtubules in the regulation of epithelial junctions

“…Microtubule affinity-regulating kinases (MARKs) are an evolutionarily conserved family of kinases that comprise MARK1(PAR-1c), MARK2 (PAR-1b/EMK), MARK3 (PAR-1a/C-TAK1) and MARK4 (PAR-1d/MARKL1). 152 Mammalian MARKs are homologous to the invertebrate partitioning gene product Par-1, which regulates development of cell polarity, 153 and belong to the same family of energy sensing kinases as AMPK. 154 MARKs are indirectly associated with MTs, since they were identified as kinases that phosphorylate the MT-regulating proteins tau and MAPs, to regulate MT dynamics and MT-dependent transport.…”

The kinases PIG-1 and PAR-1 act in redundant pathways to regulate asymmetric division in the EMS blastomere ofC. elegans

“…Polarization kinetics are slower when one of those mechanisms is compromised. Further, although an anterior PAR domain can be established in the absence of PAR-2, PAR-2 is essential during the maintenance phase to prevent anterior PARs from invading the posterior domain (Rose and Gonczy, 2014;Wu and Griffin, 2017). Previous studies showed a weaker effect on polarity maintenance in par-1 mutants compared to par-2 mutants (Cuenca et al, 2003).…”

“…Several of the PAR polarity proteins are polarized along the anterior/posterior (AP) axis during polarity establishment. The PDZ-containing proteins PAR-3 and PAR-6 and the atypical protein kinase C, PKC-3, initially localize uniformly around the entire cell cortex, then become localized to the anterior domain, allowing PAR-2, a RING-finger protein, and PAR-1, a Ser/Thr kinase, localize to the reciprocal posterior domain of the embryo (Goldstein and Macara, 2007;Rose and Gonczy, 2014;Wu and Griffin, 2017). Following their establishment in these domains, PAR proteins mutually exclude each other from their distinct anterior and posterior domains to maintain cell polarity.…”

Microtubule-Based Mechanisms of Pronuclear Positioning

“…Due to its powerful genetic tool kit and optically tractable eggs, C. elegans is one of the most thoroughly studied models for the assembly and migration of sperm asters. C. elegans eggs represent ã 50 µm oval-shaped cell type, consisting of the future anterior end containing the maternal meiotic spindle and the future posterior end where fertilization and entry of the male pronucleus occurs ( Figure 1A) [9]. The unfertilized egg is arrested in meiosis I, which resumes upon fertilization resulting in formation of the female pronucleus upon meiotic completion [10].…”