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Crosstalk between small GTPases and polarity proteins in cell polarization

Key Points

  • Three sets of conserved polarity proteins — the partitioning defective (PAR), Scribble and Crumbs complexes — regulate polarization processes in many different cell types and organisms, including worms, flies, fish, frogs and mammals.

  • Small GTPases of the Rho family are potent modulators of the actin and microtubule cytoskeleton.

  • Recent data indicate that the Ras-like RAP1 protein and various Rho proteins crosstalk to polarity proteins to induce spatially restricted cytoskeletal remodelling. This is required for cell polarization in different cellular contexts.

  • The processes that regulate polarization of neuronal cells, T cells and epithelial cells show striking similarities but also cell-type-specific differences. In these various cell types, polarity signalling involves the concerted action of different polarity proteins and different small GTPases, including their regulatory and effector proteins.

  • RhoA activity promotes cell contractility, whereas RAC1 and CDC42 signalling induces the formation of cellular protrusions. RAC1 can suppress RhoA activity and vice versa, a phenomenon that is known as Rho–Rac antagonism and that is crucial during polarization and migration of cells.

  • RhoA can modulate the activity of the PAR polarity complex, and recent studies implicate components of the PAR3 complex in balancing Rho–Rac antagonism by controlling regulatory proteins of RhoA.

  • Recently identified molecular links between signalling by polarity proteins and Rho GTPases have provided intriguing insights into the cell polarization processes that are essential for the normal behaviour of cells or the aberrant behaviour of cancer cells.

Abstract

Cell polarization is crucial for the development of multicellular organisms, and aberrant cell polarization contributes to various diseases, including cancer. How cell polarity is established and how it is maintained remain fascinating questions. Conserved proteins of the partitioning defective (PAR), Scribble and Crumbs complexes guide the establishment of cell polarity in various organisms. Moreover, GTPases that regulate actin cytoskeletal dynamics have been implicated in cell polarization. Recent findings provide insights into polarization mechanisms and show intriguing crosstalk between small GTPases and members of polarity complexes in regulating cell polarization in different cellular contexts and cell types.

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Figure 1: Effectors of Rho GTPases.
Figure 2: Crosstalk between small GTPases and the PAR complex mediates different aspects of neuronal polarity.
Figure 3: Crosstalk between small GTPases and polarity proteins controls front–rear polarization of T cells.
Figure 4: Crosstalk between Rho GTPases and polarity proteins during the formation and loss of epithelial apico–basal cell polarity.
Figure 5: Crosstalk between small GTPases and polarity proteins controls front–rear polarization of epithelial cells, astrocytes and fibroblasts.
Figure 6: The PAR complex has a central role in balancing GTPase function during cellular polarization.

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Acknowledgements

We apologize to all those authors whose papers we could not cite because of space limitations. We thank A. Gerard for helpful comments. Work in our laboratory is supported by the Seventh Framework Program of the European Commission (TuMIC) and by grants from the Dutch Cancer Society to J.G.C.

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Glossary

GTPase effector

A protein that directly binds to the GTPase in a GTP-dependent manner, and mediates downstream signalling.

Epithelial–mesenchymal transition

(EMT). A developmental programme, during which epithelial cells adopt a mesenchymal phenotype that is marked by the loss of intercellular adhesion and by increased cell migration. During EMT, epithelial marker proteins, such as E-cadherin, are downregulated, whereas mesenchymal markers, including vimentin, are upregulated.

Apico–basal polarity

The polarity axis along the apical (uppermost) plasma membrane domain and the basal plasma membrane. In epithelial cells, the basolateral plasma membrane contains different components than the apical plasma membrane, and vesicular trafficking in part occurs along different apical and basolateral routes.

Actomyosin contractility

Myosin-II multimers that are associated with actin filaments can generate contractility by antiparallel sliding of actin filaments. Actomyosin meshworks provide the cell with mechanical stability and are required during cell division, cell migration and cell polarization processes.

Dendritic spine

A small, actin-rich membrane extrusion that is found along dendrites and forms the postsynaptic terminal, a part of the neuronal synapse. Spines are frequently remodelled in response to neuronal signals.

Stress fibre

A structure at the base of a cell that mediates contractile forces and consists of axial filamentous actin bundles that are associated with myosin-II molecules.

Lamellipodium

A sheet-like cellular protrusion that is enriched in branched filamentous actin and is often observed at the front of migrating cells.

Filopodium

A thin, actin-rich plasma membrane protrusion that is often observed in motile cells and sometimes precedes lamellipodium formation.

Growth cone

The large cone-shaped motile tip of the developing axon or dendrite.

Phosphatidylinositol-3,4,5-trisphosphate

(PtdIns(3,4,5)P3). A phospholipid component of cellular membranes that is involved in signalling processes and that serves as a binding site for pleckstrin homology domain-containing proteins.

Pleckstrin-homology (PH) domain

A protein domain with high affinity for phosphatidylinositol-3,4,5-trisphosphate.

Uropod

A large membrane protrusion at the rear of polarized leukocytes that is implicated in many processes, including T-cell activation, cell–cell adhesion and leukocyte migration.

Antigen-presenting cell

An immune cell, such as a B cell, a dendritic cell or a macrophage, that presents fragments of foreign proteins on the cell surface to initiate an immune response. These fragments are bound to major histocompatibility complex (MHC) class II molecules. T cells can recognize the MHC class II–antigen complex through their T-cell receptor, and might subsequently become activated.

Adherens junction

An adhesive intercellular contact site that mediates mechanical stability. Cadherin molecules of adjacent cells bind to each other, and are coupled to the actin cytoskeleton by their cytoplasmic domains.

Classical cadherin

A Ca2+-dependent transmembrane adhesion protein that mediates intercellular adhesion in many different cell types. The extracellular domains of classical cadherins form homotypic dimers with cadherins on opposing cells, and the intracellular protein domain interacts with many cytoplasmic proteins, including members of the catenin family.

Tight junction

A selective barrier in epithelial cells that prevents the free diffusion of soluble molecules and membrane components through the intercellular space and within different membrane domains, respectively.

Nectin

A member of a family of Ca2+-independent, immunoglobulin-like, transmembrane molecules that mediate adhesion between cells.

Glial cell

A non-neuronal cell of the brain (such as an astrocyte, an oligodendrocyte or a Schwann cell) that provides nutrients to neurons, forms myelin and contributes to axon guidance and neuronal signalling.

Dynein

A minus-end-directed microtubule motor protein that consists of several subunits. Dynein is required for various cellular processes, including organelle positioning and vesicle transport along microtubules.

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Iden, S., Collard, J. Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol 9, 846–859 (2008). https://doi.org/10.1038/nrm2521

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