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PKC and the control of localized signal dynamics

Nature Reviews Molecular Cell Biology volume 11, pages 103–112 (2010)Cite this article

Subjects

Key Points

  • The protein kinase C (PKC) family of lipid-activated protein kinases lend themselves to compartmentalized action, a property of signalling systems that is increasingly recognized as crucial in determining dynamic cellular behaviour. The Review exemplifies how PKC isoforms can influence such localized signals.

  • The modular nature of PKCs allows PKC activity to be deployed with spatial and temporal specificity. It also allows PKC activity to be directed by multiple inputs, including localized (membrane limited) second messenger production and interaction with membrane-anchored small G proteins, scaffolds and accessory proteins.

  • The relationship between PKC action and associated signalling events in cell–cell interaction are exemplified by the roles of PKCθ in the interaction of T cells with peptide-bound antigen-presenting cells, as well as the role of atypical PKCs (aPKCs) in cell polarity.

  • The localized behaviour of signals under PKC control are illustrated by particular examples of migratory behaviour, including MET-dependent migration involving PKCα and PKCɛ, and aPKC-dependent migration.

  • Our ability to locally interfere with signals to provide evidence of necessity and sufficiency has been limited by a lack of appropriate experimental methodologies. Strategies are necessary that allow the manipulation of spatial and dynamic behaviour in a physiological context.

Abstract

Networks of signal transducers determine the conversion of environmental cues into cellular actions. Among the main players in these networks are protein kinases, which can acutely and reversibly modify protein functions to influence cellular events. One group of kinases, the protein kinase C (PKC) family, have been increasingly implicated in the organization of signal propagation, particularly in the spatial distribution of signals. Examples of where and how various PKC isoforms direct this tier of signal organization are becoming more evident.

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Figure 1: The protein kinase C superfamily.
Figure 2: Protein kinase C and polarizing signals.
Figure 3: Protein kinase C isoforms influence MET signals.
Figure 4: Localized signals controlled by PKCζ and PKCι during cell migration.

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Authors and Affiliations

  1. Protein Phosphorylation Laboratory, London Research Institute Cancer Research UK, 44 Lincoln's Inn Fields, WC2A 3PX, London, UK

    Carine Rosse, Mark Linch, Angus J. M. Cameron, Katrina Boeckeler & Peter J. Parker

  2. Department of Tumour Biology, Cancer Research UK Clinical Centre, Bart's and the London Queen Mary's School of Medicine and Dentistry, EC1M 6BQ, London, UK

    Stéphanie Kermorgant

  3. Division of Cancer Studies, King's College London, Guy's Hospital, SE1 1UL, London, UK

    Peter J. Parker

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  1. Carine Rosse
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Glossary

Allosteric mechanism

A mechanism by which a protein is regulated by a change in its shape and activity after binding an effector molecule at a site other than its active site.

Phox/Bem 1 (PB1) domain

Protein module that can bind to target proteins through a PB1–PB1 domain interaction.

Antigen-presenting cell

A cell of the immune system (a macrophage, dendritic cell or B cell) that stimulates immune responses by displaying antigens on its surface to other cells of the immune system (T cells).

TH1

(T helper 1). A subset of CD4+ T helper cells that produce the cytokines interferon-γ, interleukin-2 (IL-2) and IL-12 and promote cell-mediated immunity.

TH2

(T helper 2). A subset of CD4+ T helper cells that produce cytokines such as interleukin-4 (IL-4),IL-5,IL-6,IL-10 and IL-13, leading to activation of humoral immune responses.

TH17

(T helper 17). A subset of CD4+ T helper cells that produce cytokines such as interleukin-17 (IL-17),IL-21 and IL-22. They are thought to be important in inflammatory and autoimmune diseases.

Supramolecular activation complex

Areas of the immunological synapse in which T cell receptors, integrins and other cell surface proteins have segregated into distinct areas.

Total internal reflection fluorescence

A microscope exploiting evanescent wave excitation of the thin region (∼100nm) at the contact area between a specimen and the glass coverslip (of distinct refractive index).

Anergy

The impaired or absent ability of an immune cell to respond to specific antigens.

Tight junction

Closely associated area of two cells, the membranes of which join to form a barrier to fluids and molecules.

Basolateral membrane

The layer of plasma membrane of epithelial cells that forms its basal (base) and lateral (side) surfaces.

Apical–basal polarity

The unequal distribution of proteins and other materials between the apical side (facing the exterior) and the basal side (facing the interior) in epithelial cells.

PDZ domain

A protein-interaction domain (also known as DHR or GLGF domain) that is often found in multi-domain scaffolding proteins and holds together signalling complexes.

Clathrin

A protein that forms a lattice-shaped coating on coated pits and coated vesicles during endocytosis.

Dynamin

A large GTPase involved in the scission of nascent vesicles from parent membranes.

Early endosome

Small irregularly shaped intracellular vesicle to which endocytosed molecules are initially delivered.

Focal adhesion

Large macromolecular assembly through which both mechanical force and regulatory signals are transmitted between the cell and the extracellular matrix.

Convergent extension

A process during gastrulation in which layers of cells converge and extend by a rearrangement of the cells of the ventral part of the epithelium towards the ventral midline.

Leading edge

The area of a motile cell that is closest to the direction of movement.

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Rosse, C., Linch, M., Kermorgant, S. et al. PKC and the control of localized signal dynamics. Nat Rev Mol Cell Biol 11, 103–112 (2010). https://doi.org/10.1038/nrm2847

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