Ribosomal s6 kinase

Ribosomal S6 kinase (RSK) is a family of protein serine/threonine kinases involved in the signal transduction pathways that regulate cell growth, cell proliferation, cell differentiation, cell survival, and cell motility. The RSK family members are activated in response to various growth factors, peptide hormones, and neurotransmitters, and they are known to play a critical role in the control of the cell cycle and in the regulation of cellular RNA and protein synthesis.

Structure

RSK proteins are composed of two nonidentical kinase domains: a C-terminal kinase domain (CTKD) that resembles those found in the AGC (PKA/PKG/PKC) family of kinases, and an N-terminal kinase domain (NTKD) that is unique to the RSK family. The NTKD is responsible for the phosphorylation and activation of the CTKD. The activation of RSK is mediated by the extracellular signal-regulated kinases 1 and 2 (ERK1/2), which phosphorylate the CTKD.

Function

The primary function of RSK is to mediate the cellular responses to extracellular signals. Once activated, RSK phosphorylates a variety of substrates, including transcription factors, such as CREB (cAMP response element-binding protein), and other kinases, such as BAD (Bcl-2-associated death promoter) and S6 kinase. Through these phosphorylation events, RSK regulates gene expression, cell growth, and survival. RSK is also involved in the regulation of cell motility by phosphorylating proteins that control cytoskeletal reorganization.

Clinical Significance

Alterations in RSK activity have been implicated in the development and progression of several human diseases, including cancer. Overexpression or hyperactivation of RSK has been observed in various types of cancer, where it promotes cell proliferation, survival, and metastasis. Consequently, RSK is considered a potential target for cancer therapy, and several small molecule inhibitors of RSK are currently under investigation.

Isoforms

There are four isoforms of RSK in humans: RSK1, RSK2, RSK3, and RSK4, which are encoded by different genes. These isoforms share a high degree of structural similarity but differ in their tissue distribution and in their response to extracellular signals. For example, mutations in the gene encoding RSK2 are responsible for Coffin-Lowry syndrome, a rare genetic disorder characterized by intellectual disability and skeletal abnormalities.

Research

Research on RSK is focused on understanding its role in normal cellular physiology and in disease states, particularly cancer. Studies are also aimed at identifying and characterizing RSK substrates and at developing specific inhibitors that can modulate RSK activity for therapeutic purposes.

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