RPS6KA1

RPS6KA1 (RSK1) is a p90 ribosomal S6 kinase that operates downstream of the Mos/MAPK cascade; in Xenopus oocytes, Rsk1 activation downstream of Mos-MAPK is required for cytostatic factor (CSF)-mediated metaphase II arrest during meiosis [bio_10.1101_2025.10.03.680315]. A gain-of-function mutational substructure in RSK1 disrupts the MAPK1–RSK1 protein–protein interaction, resulting in aberrant MAPK1 activation and upregulation of the immune checkpoint receptor PD-1 [bio_10.1101_2025.04.17.649336].

1. 2025 Medium

   The question of how RSK1 participates in meiotic cell-cycle control was addressed by showing that Mos-MAPK-Rsk1/2 pathway activation is essential for metaphase II arrest, and that upstream Greatwall kinase depletion causes PP2A-B55 hyperactivation, insufficient Mos accumulation, and failure of Rsk1 activation.

   Evidence Greatwall kinase depletion in Xenopus oocytes with functional readouts of CDK1 activity and meiotic progression (preprint)

   PMID:bio_10.1101_2025.10.03.680315

   Open questions at the time

   • Direct substrates of RSK1 that enforce CSF arrest remain unidentified
   • Whether RSK1 and RSK2 have non-redundant roles in meiosis is unresolved
   • Findings are from a single Xenopus oocyte study; confirmation in mammalian oocytes is lacking
2. 2025 Medium

   It was unknown how specific RSK1 mutations could produce gain-of-function phenotypes; tiling base-editing mutagenesis revealed that pathogenic mutations in a defined RSK1 substructure disrupt the MAPK1–RSK1 protein–protein interaction, liberating MAPK1 activity and driving PD-1 upregulation.

   Evidence Base-editing tiling mutagenesis screen with computational PPI disruption analysis and PD-1 expression readout in human cells (preprint)

   PMID:bio_10.1101_2025.04.17.649336

   Open questions at the time

   • The structural basis of the MAPK1–RSK1 interaction disrupted by these mutations has not been resolved at atomic resolution
   • Whether the PD-1 upregulation is a direct transcriptional consequence of MAPK1 hyperactivation or involves additional intermediates is unknown
   • Independent validation of the PPI disruption by orthogonal biochemical methods (e.g., co-immunoprecipitation, SPR) has not been reported
3. 2025 Low

   RSK1/2 were identified as activated kinases in chemotherapy-resistant triple-negative breast cancer cells, raising the question of whether RSK1 functionally contributes to resistance.

   Evidence Phospho-antibody arrays in TNBC cell lines following chemotherapy dose escalation (preprint)

   PMID:bio_10.1101_2025.11.01.685128

   Open questions at the time

   • RSK1 activation was detected by a single antibody-array approach without direct mechanistic dissection of RSK1 specifically
   • Functional requirement of RSK1 for chemoresistance (e.g., by genetic ablation or pharmacological inhibition) was not tested
   • The relevant RSK1 substrates in resistant cells are unknown

• The direct substrates and downstream transcriptional programs through which RSK1 enforces meiotic arrest, regulates PD-1 expression, and potentially contributes to chemoresistance remain undefined.
• No systematic substrate identification for RSK1 has been reported in the timeline
• Structural model of the MAPK1–RSK1 interface is lacking
• In vivo physiological roles of RSK1 distinct from RSK2 have not been delineated