Ribosomal protein S6 kinase alpha-1 and alpha-3 (RSK1/2)

RSK1/2 (Ribosomal protein S6 kinase alpha-1 and alpha-3) are key serine/threonine kinases within the p90 ribosomal S6 kinase (p90RSK) family [2, 3]. They act as essential downstream effectors of the Ras/MAPK signaling pathway, where they are activated by ERK1/2 and PDK1 to regulate fundamental cellular processes including growth, survival, and motility [1, 4]. In many human cancers, such as triple-negative breast cancer and acute myeloid leukemia, RSK1/2 are frequently hyperactivated, driving oncogenic progression and resistance to therapy [5, 8, 11]. Beyond their role in oncology, RSK2 is critically involved in neurodevelopment, with mutations in the RPS6KA3 gene causing Coffin-Lowry syndrome, a condition marked by intellectual disability [10, 12]. Pharmacological inhibition of RSK1/2 is being explored as a therapeutic strategy, with small-molecule inhibitors like PMD-026 currently in clinical trials [2, 13]. These inhibitors offer a potentially safer alternative to upstream MAPK pathway inhibitors by targeting a more restricted set of substrates [8]. RSK1 and RSK2 also play distinct roles in cell adhesion and immune response, respectively, suggesting that isoform-specific targeting might be beneficial in certain contexts [7]. Overall, RSK1/2 represent a significant therapeutic node at the convergence of multiple signaling pathways [2, 4].

Other names

p90RSKRPS6KA1RPS6KA3MAPKAPK1AMAPKAPK1BRSK1RSK2

Inhibition of kinase activity through ATP-competitive or allosteric binding to the N-terminal or C-terminal kinase domains