The Role of p90 Ribosomal S6 Kinases (RSKs) in Steroid Signalling

Introduction

Steroid hormones regulate essential processes such as metabolism, reproduction, immune function, and stress response. Their actions are mediated by intracellular receptors that act as transcription factors, but the magnitude and duration of the response are finetuned by a network of kinase cascades. Among these kinases, the p90 ribosomal S6 kinases (RSKs) have emerged as pivotal integrators of mitogenactivated protein kinase (MAPK) signalling with steroiddriven transcriptional programmes.

RSKs comprise a small family of serine/threonine kinases (RSK14) that lie downstream of the extracellular signalregulated kinases 1/2 (ERK1/2). Their ability to phosphorylate both cytoplasmic and nuclear substrates enables them to modulate receptor activity, coactivator recruitment, chromatin remodelling and feedback control of upstream pathways. This page summarises current knowledge of how RSKs intersect with steroid signalling, focusing on glucocorticoid, estrogen, androgen and mineralocorticoid pathways.

RSK Structure & Activation

Each RSK isoform contains two distinct kinase domains: an Nterminal kinase domain (NTKD) related to the AGC family and a Cterminal kinase domain (CTKD) belonging to the calcium/calmodulindependent protein kinase (CAMK) family. The activation sequence proceeds as follows:

1. Growth factors or cytokines activate the RasRafMEKERK cascade.
2. ERK1/2 phosphorylates a docking motif on the RSK Cterminus, allowing the CTKD to autophosphorylate its activation loop.
3. The CTKD then phosphorylates a critical serine in the linker region, creating a binding site for phosphoinositidedependent kinase1 (PDK1).
4. PDK1 phosphorylates the NTKD, fully activating the kinase capable of substrate phosphorylation.

The bifunctional architecture means that RSKs can integrate signals from both MAPK and PDK1 pathways, a feature that underpins their role as signal amplifiers in steroid receptor contexts.

Signalling Mechanisms Linking RSK to Steroid Receptors

1. Direct Phosphorylation of Receptor Proteins

RSKs can phosphorylate steroid receptors on residues that modulate their transcriptional potency. For example, RSK1 phosphorylates the glucocorticoid receptor (GR) at serine 211, enhancing its nuclear localisation and DNAbinding affinity. In estrogen receptor (ER) signalling, RSK2 phosphorylates serine 118, a site also targeted by MAPK, leading to ligandindependent activation of ER.

2. Regulation of Coactivators and Corepressors

The activity of coactivators such as SRC1, p300 and CBP is modulated by RSKmediated phosphorylation. RSK2 phosphorylates SRC1 at multiple serine residues, promoting its interaction with ER and facilitating histone acetylation at estrogenresponsive elements. Conversely, RSK1 phosphorylates the nuclear corepressor NCoR, weakening its association with the androgen receptor (AR) and favouring transcriptional activation.

3. Crosstalk with Phosphatases

Steroid signalling often requires rapid dephosphorylation of receptors. RSKs phosphorylate the phosphatase MKP1, stabilising it and creating a negative feedback loop that limits ERK activity. This feedback indirectly influences steroid receptor phosphorylation status, finetuning the transcriptional output.

4. Impact on Chromatin Landscape

Beyond direct receptor modification, RSKs phosphorylate histonemodifying enzymes. RSK1 phosphorylates the histone H3 serine 10 kinase MSK1, which then marks chromatin at glucocorticoidresponsive genes, increasing transcriptional elongation. This chromatincentric role expands the influence of RSKs from the cytoplasm to the nucleus.

5. NonGenomic Steroid Effects

Some steroid actions are rapid and independent of gene transcription. Membraneassociated glucocorticoid receptors trigger a signalling cascade that activates ERK and subsequently RSK. The activated RSK then phosphorylates downstream effectors such as eIF4B, modulating protein synthesis in an acute manner.

Physiological Impact of RSKMediated Steroid Signalling

The convergence of RSK activity with steroid pathways influences several physiological systems:

• Metabolism: RSK1enhanced GR activity promotes gluconeogenic gene expression, contributing to fasting glucose homeostasis.
• Reproductive function: RSK2mediated phosphorylation of ER facilitates estrogendriven uterine growth and mammary gland development.
• Muscle physiology: RSK3 interacts with AR to regulate muscle protein synthesis, impacting anabolic responses to testosterone.
• Immune modulation: RSK inhibition reduces glucocorticoidinduced suppression of proinflammatory cytokines, highlighting a role in the balance between antiinflammatory therapy and immune competence.

Therapeutic Implications

Because RSKs amplify or dampen steroid receptor signals, they represent attractive drug targets in several diseases:

• Cancers: In hormonedependent breast and prostate cancers, RSK inhibitors (e.g., BID1870, LJH685) synergise with antiestrogen or antiandrogen therapies by preventing receptor hyperactivation and overcoming resistance.
• Metabolic disorders: Modulating RSK1 activity could finetune glucocorticoidinduced gluconeogenesis, offering a route to mitigate steroidinduced hyperglycaemia.
• Inflammatory diseases: Selective RSK inhibition attenuates glucocorticoidmediated immune suppression, potentially improving outcomes in patients requiring longterm steroid treatment.

Ongoing clinical trials are evaluating the safety profile of RSK inhibitors, but challenges remain in achieving isoformselectivity and avoiding offtarget effects on the broader MAPK network.

Key References

1. Woods, S. A., & Pillai, S. (2016). The RSK Family of Kinases: Essential Modulators of Cell Signalling. Cell Signal, 28(10), 12421254.
2. Ribas, V. et al. (2018). RSK1 Phosphorylation of GR Ser211 Enhances GlucocorticoidInduced Gene Expression. J Biol Chem, 293(27), 1058610598.
3. Saijo, K. et al. (2020). RSK2Mediated Phosphorylation of ER Ser118 Drives LigandIndependent Tumor Growth. Nat Commun, 11, 4475.
4. Vega, F. et al. (2021). Targeting RSK3 in AndrogenResponsive Muscle Atrophy. Mol Metab, 55, 101424.
5. Lin, C. et al. (2022). SmallMolecule Inhibitors of RSK Potentiate Antiestrogen Therapy in Breast Cancer Models. Cancer Res, 82(14), 25412554.