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  • Review Article
  • Published:

Parsing the Polarity Code

Nature Reviews Molecular Cell Biology volume 5, pages 220–231 (2004)Cite this article

Key Points

  • The molecular mechanisms that drive cell polarization are remarkably conserved throughout metazoans. A group of genes (called the par genes), first discovered in the nematode Caenorhabditis elegans, is now known to regulate cell polarity in diverse organisms and in many different contexts.

  • The par genes encode a diverse set of proteins that includes kinases, scaffold, adaptor and zinc-finger proteins. Surprisingly, many of them physically interact with each other.

  • The PAR proteins also interact physically with other sets of polarity proteins including Lethal giant larvae (LGL1/2) and PALS1 (protein associated with LIN7), which have been implicated in epithelial cell polarization.

  • A PDZ-domain protein called PAR6 functions as a targeting subunit for the atypical protein kinase C (aPKC), and binds to PAR3, LGL1/2 and PALS1. It also binds to, and is regulated by, a small GTPase, CDC42.

  • CDC42 has a key role in the polarization of budding yeast and in many other polarity processes in animal cells, such as in neutrophil chemotaxis.

  • The PAR proteins and their binding partners also function in asymmetric cell division, by controlling the orientation of the mitotic spindle.

  • Downstream of the PAR proteins is a complex that includes the Gα subunits of the heterotrimeric G-proteins, and a protein called PINS.

  • In vertebrates, PINS binds to a large nuclear protein called NuMA, which stabilizes microtubules and is required for the organization of the mitotic spindle poles.

  • PINS and Gα somehow conspire to attach and/or regulate the pulling forces on aster microtubules that attach the spindle poles to the cell cortex. These pulling forces position and orientate the poles.

  • In cells in which the cell fate determinants have been polarized along the same axis as the orientated spindle poles, cell division segregates the determinants into different daughters.

  • Cell polarization involves new signal transduction networks that interact in complex ways with the actin and tubulin cytoskeletal filaments and the plasma membrane to generate asymmetric structures.

Abstract

Cell polarization is used both to mediate physical fates, as, for example, in orientated cell migration, and to specify differential phenotypic fates, as in the asymmetric division of stem cells. Strikingly, the same sets of conserved proteins are used throughout the Metazoa for these purposes. The PAR proteins organize cell polarization in many contexts, and the PINS proteins control the orientation of mitosis. These proteins seem to function as components of a self-organizing network, and an important goal is to decode — or parse — the molecular language of this network.

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Figure 1: Symmetric and asymmetric cell divisions.
Figure 2: The PAR proteins and their interactions.
Figure 3: Biological functions of CDC42 and the PAR6–PAR3–aPKC complex.
Figure 4: Mechanism of activation of CDC42 during neutrophil chemotaxis.
Figure 5: Comparative structure and polarity-protein localization in Drosophila melanogaster and vertebrate epithelial cells.
Figure 6: The Crumbs polarity complex.
Figure 7: The Scribble, Discs large and Lethal giant larvae polarity proteins.
Figure 8: Interactions of PAR6 with its known binding partners.
Figure 9: Distribution of the PAR proteins in the Caenorhabditis elegans zygote.

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Acknowledgements

I am grateful to Q. Du, A. Spang and D. Lannigan for critical reading of the manuscript, to those who provided invaluable information before publication, and for support from the National Cancer Institute, Department of Health and Human Services. Cell polarity is a large and rapidly growing field, and I regret that it was impossible to cite numerous important papers.

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  1. Department of Microbiology, Center for Cell Signaling, University of Virginia, Health Sciences Center, Charlottesville, 22908-0577, Virginia, USA

    Ian G. Macara

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  1. Ian G. Macara
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DATABASES

Locuslink

par

pkc3

Flybase

14-3-3ε

Bazooka

Crb

Dlg

Insc

Jar

Lgl

Lkb1

Mira

Par1

Par6

Pins

Scrib

Sdt

Zip

Saccharomyces genome database

Cdc42

Swiss-Prot

AGS3

GSK3β

LGN

PAK1

PIXα

Glossary

ISOTROPIC

Identical in all directions; invariant with respect to direction.

TESSELLATION

A checkered or mosaic pattern of polygons that are arranged on a surface in such a way as to leave no region uncovered. The word 'tessellate' is derived from the Ionic version of the Greek word 'tesseres', which, in English, means 'four'. The first tilings were made from square tiles.

APICAL SURFACE

The surface of an epithelial or endothelial cell that faces the lumen of a cavity or tube, or the outside of the organism.

BASOLATERAL SURFACE

The surface of an epithelial cell that adjoins underlying tissue.

MITOTIC SPINDLE

A highly dynamic bipolar array of microtubules that forms during mitosis or meiosis and is used to move the duplicated chromosomes apart.

PLANAR POLARITY

The polarity of cells in the plane of an epithelium.

14-3-3 PROTEIN

A regulatory protein that binds to phosphorylated forms of various proteins that are involved in signal transduction and cell-cycle control.

RHO-FAMILY GTPases

A subfamily of small (∼21 kDa) GTP-binding proteins that are related to Ras, and that regulate the cytoskeleton. The nucleotide-bound state is regulated by GTPase-activating proteins, which catalyse hydrolysis of the bound GTP, and guanine nucleotide-exchange factors, which catalyse GDP–GTP exchange.

ASTRAL MICROTUBULES

Microtubules that radiate from the mitotic spindle poles to the cell cortex. They are involved in positioning and alignment of the spindle poles during cell division.

LEADING EDGE

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to a depth of about 1 μm into the lamellipodium.

PDZ DOMAIN

Protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family (Postsynaptic-density protein of 95 kDa (PSD95), Discs large (Dlg) and Zona occludens-1 (ZO 1)).

TIGHT JUNCTION

A belt-like region of adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing in the plane of the membrane.

ADHERENS JUNCTION

A cell–cell adhesion complex that contains cadherins and catenins that are attached to cytoplasmic actin filaments.

MARGINAL ZONE

The most apical region of cell–cell contact in D. melanogaster epithelia. It is a boundary region between the free apical surface of the cells and the adherens junction (zona adherens) that forms the primary cell–cell attachment.

ASTROCYTES

Star-shaped glial cells that support the tissue of the central nervous system.

MITOTIC CATASTROPHE

Cell death that occurs as a consequence of defective mitosis, usually because of a failure in chromosome segregation.

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Macara, I. Parsing the Polarity Code. Nat Rev Mol Cell Biol 5, 220–231 (2004). https://doi.org/10.1038/nrm1332

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