Ribosomal protein S6 kinase alpha (RSK) (RSK)

The Ribosomal S6 kinase (RSK) family consists of four human isoforms (RSK1-4) of highly conserved serine/threonine kinases that function as downstream effectors of the Ras-extracellular signal-regulated kinase (ERK) pathway (UniProt: P23443, P51812). These enzymes are structurally unique, featuring two distinct, functional kinase domains in a single polypeptide chain: an N-terminal kinase domain (NTKD) and a C-terminal kinase domain (CTKD). RSKs play a critical role in regulating cell growth, motility, survival, and proliferation by phosphorylating various substrates, including transcription factors, epigenetic regulators, and the protein translation machinery (PMID: 22430205). In oncology, RSK isoforms are frequently overexpressed or hyperactivated, contributing to tumor progression and drug resistance in breast, lung, and prostate cancers. Additionally, mutations in the RSK2 gene are the primary cause of Coffin-Lowry syndrome, a rare genetic disorder characterized by intellectual disability and skeletal abnormalities (PMID: 10633131). Therapeutic targeting of RSK focuses on small-molecule inhibitors that bind to either the NTKD or CTKD to disrupt signaling, with compounds like PMD-026 currently undergoing clinical evaluation (ClinicalTrials.gov: NCT04115306).

Other names

p90 ribosomal S6 kinasep90RSKMAPK-activated protein kinase 1MAPKAP-K1Ribosomal protein S6 kinase alpha

Inhibition of the N-terminal or C-terminal kinase domains to prevent phosphorylation of downstream substrates in the MAPK signaling pathway.