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Philos Trans R Soc Lond B Biol Sci,
2013]
The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine-threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz-Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?
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F1000Res,
2017]
The scaffold protein Par-3 ( Drosophila Bazooka) is a central organizer of cell polarity across animals. This review focuses on how the clustering of Par-3 contributes to cell polarity. It begins with the Par-3 homo-oligomerization mechanism and its regulation by Par-1 phosphorylation. The role of polarized cytoskeletal networks in distributing Par-3 clusters to one end of the cell is then discussed, as is the subsequent maintenance of polarized Par-3 clusters through hindered mobility and inhibition from the opposite pole. Finally, specific roles of Par-3 clusters are reviewed, including the bundling of microtubules, the cortical docking of centrosomes, the growth and positioning of cadherin-catenin clusters, and the inhibition of the Par-6-aPKC kinase cassette. Examples are drawn from Drosophila, Caenorhabditis elegans, mammalian cell culture, and biochemical studies.
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Curr Biol,
2002]
Six par genes (
par-1 through
par-6) have been identified in Caenorhabditis elegans. Loss-of-function mutations in any par locus results in loss of anterior-posterior (AP) asymmetries during the first two embryonic cell divisions. This results in a failure to restrict developmental regulators to specific embryonic cells, mitotic spindle orientation defects and abnormal cell fate pattering. In sum, the par genes appear responsible for establishing asymmetries that define the AP body axis in C. elegans.
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Dev Cell,
2007]
The par genes were discovered in genetic screens for regulators of cytoplasmic partitioning in the early embryo of C. elegans, and encode six different proteins required for asymmetric cell division by the worm zygote. Some of the PAR proteins are localized asymmetrically and form physical complexes with one another. Strikingly, the PAR proteins have been found to regulate cell polarization in many different contexts in diverse animals, suggesting they form part of an ancient and fundamental mechanism for cell polarization. Although the picture of how the PAR proteins function remains incomplete, cell biology and biochemistry are beginning to explain how PAR proteins polarize cells.
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Science,
2002]
The eggs of Caenorhabditis elegans and Drosophila bear little similarity to each other, yet both depend on the par genes for control of anterior-posterior polarity. Here we explore possible common roles for the par genes (pars) in converting transient asymmetries into stably polarized axes. Although clear mechanistic parallels remain to be established, par-dependent regulation of microtubule dynamics and protein stability emerge as common themes.
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Development,
2011]
Cell polarity is essential for cells to divide asymmetrically, form spatially restricted subcellular structures and participate in three-dimensional multicellular organization. PAR proteins are conserved polarity regulators that function by generating cortical landmarks that establish dynamic asymmetries in the distribution of effector proteins. Here, we review recent findings on the role of PAR proteins in cell polarity in C. elegans and Drosophila, and emphasize the links that exist between PAR networks and cytoskeletal proteins that both regulate PAR protein localization and act as downstream effectors to elaborate polarity within the cell.
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FEBS J,
2021]
The Par-3/Baz family of polarity determinants is highly conserved across metazoans, and includes C. elegans PAR-3, Drosophila Bazooka (Baz), human Par-3 (PARD3) and human Par-3-like (PARD3B). The C. elegans PAR-3 protein localises to the anterior pole of asymmetrically dividing zygotes with CDC42, atypical protein kinase C (aPKC) and PAR-6. The same C. elegans 'PAR complex' can also localise in an apical ring in epithelial cells. Drosophila Baz localises to the apical pole of asymmetrically dividing neuroblasts with Cdc42-aPKC-Par-6, while in epithelial cells localises both in an apical ring with Cdc42-aPKC-Par6 as well as with E-cadherin at adherens junctions. These apical and junctional localisations have become separated in human PARD3, which is strictly apical in many epithelia, and human PARD3B, which is strictly junctional in many epithelia. We discuss the molecular basis for this fundamental difference in localisation, as well as the possible functions of Par-3/Baz family proteins as oligomeric clustering agents at the apical domain or at adherens junctions in epithelial stem cells. The evolution of Par-3 family proteins into distinct apical PARD3 and junctional PARD3B orthologs coincides with the emergence of stratified squamous epithelia in vertebrates, where PARD3B, but not PARD3, is strongly expressed in basal layer stem cells - which lack a typical apical domain. We speculate that PARD3B may contribute to clustering of E-cadherin, signalling from adherens junctions via Src family kinases, or mitotic spindle orientation by adherens junctions in response to mechanical forces.
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Bioessays,
2005]
Cells become polarized to develop functional specializations and to distribute developmental determinants unequally during division. Studies that began in the nematode C. elegans have identified a group of largely conserved proteins, called PAR proteins, that play key roles in the polarization of many different cell types. During initial stages of cell polarization, certain PAR proteins become distributed asymmetrically along the cell cortex and subsequently direct the localization and/or activity of other proteins. Here I discuss recent findings on how PAR proteins become and remain asymmetric in three different contexts during C. elegans development: anterior-posterior polarization of the one-cell embryo, apicobasal polarization of non-epithelial early embryonic cells, and apicobasal polarization of epithelial cells. Although polarity within each of these cell types requires PAR proteins, the cues and regulators of PAR asymmetry can differ. BioEssays 27:126-135, 2005. (c) 2005 Wiley Periodicals, Inc.
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Essays Biochem,
2012]
Cell polarity is crucial for many functions including cell migration, tissue organization and asymmetric cell division. In animal cells, cell polarity is controlled by the highly conserved PAR (PARtitioning defective) proteins. par genes have been identified in Caenorhabditis elegans in screens for maternal lethal mutations that disrupt cytoplasmic partitioning and asymmetric division. Although PAR proteins were identified more than 20 years ago, our understanding on how they regulate polarity and how they are regulated is still incomplete. In this chapter we review our knowledge of the processes of cell polarity establishment and maintenance, and asymmetric cell division in the early C. elegans embryo. We discuss recent findings that highlight new players in cell polarity and/or reveal the molecular details on how PAR proteins regulate polarity processes.
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Philos Trans R Soc Lond B Biol Sci,
2013]
To become polarized, cells must first 'break symmetry'. Symmetry breaking is the process by which an unpolarized, symmetric cell develops a singularity, often at the cell periphery, that is used to develop a polarity axis. The Caenorhabditis elegans zygote breaks symmetry under the influence of the sperm-donated centrosome, which causes the PAR polarity regulators to sort into distinct anterior and posterior cortical domains. Modelling analyses have shown that cortical flows induced by the centrosome combined with antagonism between anterior and posterior PARs (mutual exclusion) are sufficient, in principle, to break symmetry, provided that anterior and posterior PAR activities are precisely balanced. Experimental evidence indicates, however, that the system is surprisingly robust to changes in cortical flows, mutual exclusion and PAR balance. We suggest that this robustness derives from redundant symmetry-breaking inputs that engage two positive feedback loops mediated by the anterior and posterior PAR proteins. In particular, the PAR-2 feedback loop stabilizes the polarized state by creating a domain where posterior PARs are immune to exclusion by anterior PARs. The two feedback loops in the PAR network share characteristics with the two feedback loops in the Cdc42 polarization network of Saccharomyces cerevisiae.