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The nuts and bolts of AGC protein kinases

Key Points

  • There are 60 members of the AGC family of protein kinases, which all share a conserved catalytic kinase domain.

  • Structural studies have revealed that although the structures of active AGC kinases are highly similar, inactive AGC kinases can adopt several conformations. Most described structures to date are of the catalytic domain; further work is required to elucidate the structure of full length AGC kinases.

  • AGC family members are regulated in various ways, but most require phosphorylation and/or conformational changes to be activated.

  • Functional domains, other than the kinase domain, have important roles in regulating the activity and localization of AGC kinases. The functions of some of these domains have not been fully defined.

  • AGC kinases are involved in numerous cellular processes, exemplified by the large number of proteins that they can phosphorylate. Some substrates are phosphorylated only by one AGC kinase, whereas others can be phosphorylated by multiple AGC kinases.

  • Several AGC family members have been implicated in disease, and numerous drugs targeting these kinases have been developed to treat conditions such as cancer and diabetes. In addition mutations in certain AGC kinases are linked to some inherited syndromes.

Abstract

The AGC kinase subfamily of protein kinases contains 60 members, including PKA, PKG and PKC. The family comprises some intensely examined protein kinases (such as Akt, S6K, RSK, MSK, PDK1 and GRK) as well as many less well-studied enzymes (such as SGK, NDR, LATS, CRIK, SGK494, PRKX, PRKY and MAST). Research has shed new light onto the architecture and regulatory mechanisms of these kinases. In addition, AGC kinases mediate diverse and important cellular functions, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.

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Figure 1: Domain structures of AGC kinases.
Figure 2: Key structural features of AGC kinases.
Figure 3: Mechanisms of activation of Akt, S6K, PKC, MSK and RSK.
Figure 4: Mechanisms of activation of PKA, GRK, LATS and ROCK.
Figure 5: Roles of AGC kinases in cancer and diabetes.

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Acknowledgements

We thank the Medical Research Council (L.R.P., D.K., D.R.A.) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer–Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer) for financial support.

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Glossary

Hydrophobic motif

A motif found in most AGC kinases, which is located at the carboxyl terminus of the catalytic domain. It consists of a phosphorylatable Ser or Thr residue flanked by hydrophobic residues, and its phosphorylation is required for stabilization and activation of the kinase.

Turn motif

A motif found in some AGC kinases, which is located at the carboxyl terminus of the catalytic domain. It consists of a phosphorylatable Ser or Thr residue followed by a Pro residue. Its phosphorylation is required for kinase stability and may also protect the hydrophobic motif site from dephosphorylation.

Pleckstrin homology (PH) domain

A sequence of approximately100 amino acids that is present in many signalling molecules and binds to phosphatidylinositol lipids, facilitating membrane interactions.

Agonist

A molecule that binds to and stimulates a receptor to trigger a response by the cell.

Second messenger

An intracellular signalling molecule, such as cyclic AMP, diacylglycerol or inositol triphosphate, that is rapidly and transiently synthesized following receptor activation to further amplify the signal transduction cascade.

PDK1-interacting fragment (PIF) pocket

A docking site found in the kinase domain of 3-phosphoinositide-dependent protein kinase 1. It consists of basic residues, which bind the phosphorylated hydrophobic motif of a substrate, for example p70 ribosomal S6 kinase 1.

Phox homology (PX) domain

A lipid- and protein-interaction domain that consists of 100–130 amino acids and is defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.

Pseudosubstrate

A short sequence similar to that of a substrate except it lacks a phosphorylatable residue. Binding to the kinase catalytic domain prevents substrate binding and maintains the kinase in an inactive state.

Heptapeptide repeat 1 domain

An α-helical domain that forms an antiparallel coiled coil fold known as an ACC finger. It enables binding to the small G protein rho.

Coiled-coil motif

A protein structural domain that mediates subunit oligomerization. Coiled coils contain between two and five helices that twist around each other to form a supercoil.

Long-term potentiation

A long-lasting increase in the size of the postsynaptic response to synaptic transmissions, which is thought to be a key mechanism for learning and long-term memory formation in the brain.

Heterotrimeric G protein

A protein that consists of an α-subunit, which binds GTP, and β- and γ-subunits. The α-subunit is GDP bound until stimulation of GPCR signalling, when GDP is exchanged for GTP. The α-subunit subsequently dissociates from the βγ subunits, leading to the initiation of signalling through α- and βγ binding to effectors such as adenylate cyclase and phospholipase.

Farnesylation

A post-translational modification in which a farnesyl group (a hydrophobic group of three isoprene units) is conjugated to proteins, such as Ras GTPases, that contain a carboxy-terminal CAAX motif. Farnesylation promotes attachment of the modified proteins to membranes.

Palmitoylation

A post-translational modification of a protein by the covalent attachment of a palmitate (a 16-carbon saturated fatty acid) to a cysteine residue through a thioester bond. Palmitoylation promotes attachment of the modified proteins to membranes.

EF hand

A structural domain composed of two helices (E and F) that are linked by a short loop region which binds calcium.

Pseudokinase

A protein that contains a kinase-like domain but lacks at least one of the conserved residues required for catalytic activity, and therefore is predicted to be inactive. Fourty-eight pseudokinases seem to be encoded in the human genome.

DFG

A motif (Asp–Phe–Gly) that is found in subdomain VII of the kinase catalytic domain. The aspartic acid binds Mg2+ ions, which in turn coordinate the β- and γ-phosphates of ATP in the ATP-binding site. The position of the DFG motif determines kinase activity.

VAIK

A motif (Val–Ala–Ile–Lys) that is found in subdomain II of the kinase catalytic domain. The Lys residue is involved in orienting ATP by interacting with the α- and β-phosphates of ATP.

14-3-3 protein

An adaptor protein that binds to phosphorylated Ser and Thr residues, causing changes in the target protein's enzymatic activity and subcellular localization.

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Pearce, L., Komander, D. & Alessi, D. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 11, 9–22 (2010). https://doi.org/10.1038/nrm2822

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