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The RSK family of kinases: emerging roles in cellular signalling

Key Points

  • The 90 kDa ribosomal S6 kinase (RSK) family of proteins is a group of highly conserved Ser/Thr kinases that are downstream effectors of the Ras–extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling cascade.

  • The RSK family of proteins consists of four human isoforms (RSK1–4) and two structurally related homologues, mitogen- and stress-activated kinases (MSKs)-1 and -2.

  • RSK has a complex structure and several phosphorylation sites that are phosphorylated by multiple inputs, including ERK1/2, 3′-phosphoinositide dependent kinase-1 (PDK1) and autophosphorylation events.

  • Recent studies have expanded the repertoire of biological functions that are linked to the RSK family of protein kinases, ranging from the regulation of transcription, translation and protein stability to the control of cell survival, cell motility, cell growth and proliferation.

  • The important physiological roles of the RSKs have been underscored by the discovery that defects in the RSK2 gene are the cause of Coffin–Lowry syndrome.

  • Rsk2-knockout mice have impaired learning and cognitive functions, and poor coordination compared with wild-type littermates. The animals also develop a progressive skeletal disease, osteopaenia, owing to cell-autonomous defects in osteoblast activity, and are approximately 10 to 15% smaller than their wild-type litter-mates.

  • RSK inhibitors have been identified and provide additional tools for examining RSK function in vitro and in vivo. They also might provide the foundation for future drug development.

Abstract

The 90 kDa ribosomal S6 kinase (RSK) family of proteins is a group of highly conserved Ser/Thr kinases that regulate diverse cellular processes, such as cell growth, cell motility, cell survival and cell proliferation. RSKs are downstream effectors of the Ras–extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling cascade. Significant advances in the field of RSK and ERK/MAPK signalling have occurred in the past few years, including biological insights and the discovery of novel substrates and new RSK regulatory mechanisms. Collectively, these data expand the current models of RSK signalling and highlight potential directions of research in RSK-mediated survival, growth, proliferation and migration.

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Figure 1: The domain structure of RSKs.
Figure 2: A schematic model for RSK activation.
Figure 3: Current model of RSK activation.
Figure 4: Regulation of translation by RSK.
Figure 5: Regulation of the cell-cycle by RSK.

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Acknowledgements

We thank P. Roux (Institute for Research in Immunology and Cancer, University of Montreal), N. Kubica, K. Geraghty, M. Mendoza and S. Mahoney for critical reading of the manuscript. We regret not being able to cite all of the relevant references owing to space limitations.

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Glossary

Myristoylation

An irreversible, post-translational protein modification that is found in animals, plants, fungi and viruses. A myristoyl group is covalently attached by an amide bond to the α-amino group of an N-terminal amino acid of a nascent polypeptide. Myristoylation has a vital role in membrane targeting and various signal-transduction processes.

AGC kinases

A superfamily of protein kinases that comprises a number of enzymes that have a high degree of primary sequence conservation in their respective kinase domains. The group includes RSK, S6K, AKT/PKB, MSK, SGK and PRK. These kinases phosphorylate many cellular proteins and thereby regulate cellular division, survival, metabolism, migration/invasion and differentiation.

A-kinase anchor proteins

(AKAPs). A group of structurally diverse scaffold proteins that have the common function of binding to the regulatory subunit of PKA and directing the protein to discrete locations in the cell. AKAPs also bind additional signalling molecules and might coordinate multiple components of signal-transduction pathways.

Polysome

A functional unit of protein synthesis that consists of several ribosomes attached along the length of a single molecule of mRNA.

XEXD caspase-inhibitory box

Caspases are characterized by the proteolytic cleavage of their precursors and their substrates at a specific sequence, X-Glu-X-Asp, with an absolute requirement of aspartate at position P1. Therefore, inhibitors and peptide substrates of caspases are designed based on this sequence motif, which is termed the XEXD caspase box.

Anaphase promoting complex

(APC). A complex of several proteins that is activated during mitosis to initiate anaphase. The APC functions as an E3 ubiquitin ligase that marks target proteins for degradation by the 26S proteasome. The irreversibility of proteolysis is used by cells to promote cell-cycle directionality. The APC also targets the mitotic cyclins for degradation, resulting in the inactivation of mitotic CDK complexes, and promoting exit from mitosis.

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Anjum, R., Blenis, J. The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 9, 747–758 (2008). https://doi.org/10.1038/nrm2509

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