Protein Kinases: Physiological Roles in Cell Signalling

Abstract

By catalysing reversible phosphorylation of their substrates, protein kinases play pleiotropic roles in cells and act as predominant arbiters in the coordination of cellular responses to their environment. Despite large variation in biological functions between kinases, there is great structural conservation across the human kinome. Besides structural aspects, substrate specificity relies on dynamic factors such as concentration, activity and localisation. This article discusses these fundamental aspects of protein kinases as related to cellular signalling while also taking note of the less commonly discussed members of the class such as pseudokinases and ectokinases. The complexity of signalling networks is demonstrated by a discussion on the crosstalk involved between the metabolic and signal transduction pathways. By having roles in such processes as cell growth, proliferation and death, protein kinases are at the centre of the regulation of the cell and therefore also at the heart of many human diseases when dysregulated.

Key Concepts

  • Protein kinases are enzymes that catalyse the phosphorylation of a protein substrate.
  • Reversible phosphorylation is a key feature of cellular signalling.
  • There are some highly conserved structural motifs across the human kinome despite great differences in biological functions.
  • Activation of a kinase is dependent upon assembly of the regulatory spine.
  • Structural and dynamic factors contribute to substrate selectivity.
  • Kinases are present both within the cell and in extracellular spaces (ectokinases).
  • Crosstalk with other post‐translational modifications and between other pathways makes protein kinases participants in nearly every physiological process.

Keywords: protein kinase; pseudokinase; signal transduction; kinome; metabolism; phosphorylation; post‐translational modification

Figure 1. Structure of active ERK2 (PDB: 2ERK) showing the regulatory (R) spine (in red) and the catalytic (C) spine (in yellow). Also indicated is the activation loop with both pThr‐183 and pTyr‐185.
Figure 2. Simplified representations of the ERK/MAPK and PI3K/Akt signalling pathways showing some of the crosstalk between these two pathways, as discussed in the text.
Figure 3. Conventional MAPK pathways. Mitogen‐activated protein kinase (MAPK) pathways consist of a cascade of at least three kinases: a MAPK kinase kinase (MAPKKK) that activates a MAPK kinase (MAPKK), which in turn activates the MAPK that gives the pathway its name. The residues that are phosphorylated by the upstream kinase and required for full activation are indicated. A comparison of yeast and metazoan MAPK pathways exhibits a high degree of conservation between both the individual proteins and the overall organisation of the pathway. The yeast Ste5 protein acts as a scaffold to physically organise and insulate the components and functionally similar proteins also exist in metazoa (not shown).
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Further Reading

Cantley L, Hunter T, Sever R and Thorner J (2014) Signal Transduction: Principles, Pathways, and Processes. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

Lim W, Mayer B and Pawson T (2014) Cell Signaling. New York: Garland Science.

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Cormier, Kevin W., and Woodgett, James R.(Jul 2016) Protein Kinases: Physiological Roles in Cell Signalling. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002710.pub3]