Affinage

RPS6KA2

Ribosomal protein S6 kinase alpha-2 · UniProt Q15349

Length
733 aa
Mass
83.2 kDa
Annotated
2026-06-10
28 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS6KA2 (RSK3) is a nuclear-translocating p90 serine/threonine kinase that operates downstream of the EGFR/RAS/MEK/ERK cascade to control cell survival, proliferation, and stress responses (PMID:7623830, PMID:24403857, PMID:31937753). It is a growth factor- and serum-activated kinase that autophosphorylates and phosphorylates nuclear substrates including c-Fos and histones, undergoes serum-stimulated nuclear translocation via an N-terminal nuclear localization signal, and is inactivated by protein phosphatase 2A (PMID:7623830). Its catalytic activation is driven by ERK1/2 and ERK5 phosphorylation downstream of EGFR-MEK signaling (PMID:31937753). Through this circuit RSK3 phosphorylates ribosomal protein S6 to drive protein translation and proliferation (PMID:24403857, PMID:32550912), engages a TSC2-mTOR-p70S6K1-BAD survival cascade and phosphorylates BAD at Ser112 (PMID:35217648, PMID:36883564), and acts upstream of RIP3 phosphorylation during necroptosis (PMID:32162697). RSK3 binds IκBα and suppresses NF-κB by decreasing proteasome-mediated IκBα degradation, switching cell fate from TGFβ/SMAD3-induced senescence toward malignant EMT progression (PMID:34198590, PMID:38008756). Reflecting these activities, RSK3 functions as a context-dependent regulator of cancer: a tumor suppressor in ovarian cells where it restrains ERK signaling and modulates PI3K-AKT-mTOR-dependent autophagy and ferroptosis (PMID:16878154, PMID:41502518), yet a pro-survival/drug-resistance kinase in breast, pancreatic, lung, and colorectal cancers, providing a parallel survival route under PI3K/mTOR, BET, or chemotherapeutic inhibition (PMID:24403857, PMID:23635776, PMID:36883564, PMID:40112524). In vivo, RSK3 is required for ERK1/2-driven concentric cardiac myocyte hypertrophy and supports cartilage stem/progenitor proliferation and repair (PMID:26940993, PMID:32550912).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1995 High

    Established RSK3 as a distinct growth-factor-activated S/T kinase with nuclear substrates and a regulatory logic separate from RSK1, answering whether RSK3 is simply a redundant RSK family member.

    Evidence Epitope-tagged expression in COS cells, in vitro kinase and phosphatase assays, immunofluorescence in HeLa cells

    PMID:7623830

    Open questions at the time
    • The physiological upstream activator was not identified (RSK3 was not activated by ERK2 in vitro)
    • Endogenous substrate repertoire beyond c-Fos and histones unresolved
    • NLS sequence not functionally mapped
  2. 2006 Medium

    Defined a tumor-suppressor role for RPS6KA2 in ovarian cancer, showing its re-expression restrains proliferation and ERK activity, reframing it as a brake within the MAPK pathway in a specific tissue context.

    Evidence Gain- and loss-of-function (re-expression, siRNA) with colony formation, cell cycle, apoptosis, and pERK Western blots in ovarian cancer lines

    PMID:16878154

    Open questions at the time
    • Molecular mechanism of ERK suppression not defined
    • Direct substrates mediating G1 arrest not identified
    • Tissue specificity of the suppressor role unexplained
  3. 2013 High

    Placed RSK3 as an EGFR/RAS/MEK/ERK effector driving rpS6 phosphorylation and chemoresistance, recasting it as a pro-survival kinase in pancreatic and breast cancer and a parallel route to PI3K signaling.

    Evidence Kinome siRNA screen, overexpression/knockdown, apoptosis and xenograft assays, RSK and MEK inhibitors in pancreatic and breast cancer models

    PMID:23635776 PMID:24403857

    Open questions at the time
    • How the same kinase suppresses tumors in ovary but promotes survival elsewhere not reconciled
    • Direct vs indirect rpS6 phosphorylation not distinguished from S6K activity
    • Quantitative contribution to resistance versus other RSK isoforms unclear
  4. 2016 High

    Demonstrated a non-cancer in vivo requirement for RSK3 as an ERK1/2 effector in pathological cardiac hypertrophy, establishing genetic epistasis downstream of activated RAF1.

    Evidence RSK3-knockout mice crossed with Raf1(L613V) knock-in mice, cardiac morphometry and immunohistochemistry

    PMID:26940993

    Open questions at the time
    • Cardiomyocyte substrates of RSK3 in hypertrophy not identified
    • Whether the same axis operates in human cardiac disease not tested
  5. 2020 Medium

    Identified the upstream activators (ERK1/2 and ERK5) and additional substrates/partners (RIP3, rpS6), connecting RSK3 to necroptosis and progenitor proliferation and clarifying its activation logic in survival/resistance contexts.

    Evidence MEK/ERK and RSK inhibitors with siRNA, Co-IP and directionality tests, RSK3-knockout mice in necroptosis (RGC) and cartilage repair (CSPC) models

    PMID:31937753 PMID:32162697 PMID:32550912

    Open questions at the time
    • Whether RSK3 directly phosphorylates RIP3 versus acting through an intermediate not resolved
    • Structural basis of ERK5 versus ERK1/2 activation of RSK3 unknown
    • Single-lab Co-IP for RIP3 without reciprocal structural validation
  6. 2021 Medium

    Identified IκBα as a direct RSK3 binding partner and substrate, providing a molecular handle linking RSK3 to NF-κB regulation and a druggable interaction in breast cancer.

    Evidence Kinase library screen, mammalian two-hybrid, cell-based distribution assay, small-molecule complex inhibitor with proliferation/apoptosis readouts

    PMID:34198590

    Open questions at the time
    • Phosphosite on IκBα not mapped
    • Direction of NF-κB effect not resolved in this study
    • Single-lab interaction without orthogonal endogenous validation
  7. 2022 Medium

    Pinned RSK3 to BAD Ser112 phosphorylation as a pro-survival node in TNBC and showed MYSM1 as a negative upstream regulator, linking RSK3 activity to chemosensitivity.

    Evidence MYSM1 overexpression/knockdown in TNBC lines, pBAD(Ser112) Westerns, cisplatin apoptosis assays

    PMID:35217648

    Open questions at the time
    • Direct kinase-substrate relationship vs pathway-level effect not proven biochemically
    • Mechanism by which MYSM1 inactivates RSK3 not defined
  8. 2023 High

    Resolved the pro-survival cascade as ERK→RSK3→TSC2-mTOR-p70S6K1-BAD in SCLC and showed RSK3 represses NF-κB by stabilizing IκBα against proteasomal degradation, mechanistically linking RSK3 to the senescence-versus-EMT cell-fate switch downstream of TGFβ/SMAD3.

    Evidence Drug-combination screens and xenografts (SCLC); FLAG-IP mass spectrometry, proteasome activity assays, genetic rescue and intraductal xenografts (mammary epithelial)

    PMID:36883564 PMID:38008756

    Open questions at the time
    • How RSK3 decreases IκBα proteasomal degradation mechanistically unclear
    • Whether TSC2-mTOR-BAD and NF-κB axes are coordinately or independently engaged not resolved
  9. 2025 Medium

    Extended RSK3's regulatory reach to PCSK9-MAPK suppression in colorectal cancer and to PI3K-AKT-mTOR-dependent autophagy/ferroptosis control in ovarian cancer, reinforcing its context-dependent dual role.

    Evidence Co-IP/interaction assays, RSK inhibitors (BI-D1780/BI-D1870), MAPK modulation, autophagy/ferroptosis assays, miRNA regulation, in vivo tumor models

    PMID:40112524 PMID:41502518

    Open questions at the time
    • Direct PCSK9 phosphorylation vs binding-only interaction not distinguished
    • Mechanism connecting RSK3 to ferroptosis effectors not defined
    • Single-lab findings without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis for RSK3's opposite roles—tumor suppressor in ovary versus pro-survival/resistance kinase in other tissues—and a complete catalog of its direct substrates remain unresolved.
  • No structural model explaining ERK1/2 versus ERK5 activation or PP2A inactivation
  • Direct kinase-substrate relationships (IκBα, BAD, RIP3, PCSK9) need biochemical confirmation with mapped phosphosites
  • Tissue-specific determinants of suppressor versus oncogenic output not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
BADIKBAMYSM1PCSK9RIP3

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 RSK3 (RPS6KA2) is a serine/threonine kinase that, upon growth factor, serum, or phorbol ester stimulation, undergoes autophosphorylation and phosphorylates protein substrates including c-Fos and histones. Unlike RSK1, RSK3 kinase activity was NOT activated by in vitro incubation with ERK2/MAP kinase, suggesting a distinct upstream activator. RSK3 is inactivated by protein phosphatase 2A in vitro. Epitope-tagged expression in COS cells, in vitro kinase assay, in vitro phosphatase treatment, comparison with RSK1 Molecular and cellular biology High 7623830
1995 Endogenous RSK3 undergoes serum-stimulated nuclear translocation in HeLa cells, consistent with a unique N-terminal putative nuclear localization signal encoded by RSK3. Immunofluorescence with affinity-purified RSK3 antibodies in HeLa cells Molecular and cellular biology Medium 7623830
2006 Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation, reduced proliferation, caused G1 arrest, increased apoptosis, and reduced levels of phosphorylated ERK. Conversely, siRNA knockdown of RPS6KA2 in 41M cells had the opposite effects, consistent with a tumor suppressor role downstream of the MAPK pathway. Transient transfection re-expression, colony formation assay, flow cytometry (cell cycle/apoptosis), Western blot for pERK, siRNA knockdown Oncogene Medium 16878154
2013 RSK3 (RPS6KA2) acts downstream of EGFR/RAS/MEK/ERK signaling in pancreatic cancer cells and is activated by EGF independently of KRAS mutation status. RSK3 activates ribosomal protein S6 as a downstream effector, and its overexpression rescues cells from erlotinib- and gemcitabine-induced apoptosis. siRNA knockdown, overexpression, kinome-wide siRNA screen, Western blot for pathway components, apoptosis assays, pharmacological inhibition (BI-D1870) Neoplasia (New York, N.Y.) Medium 24403857
2013 Overexpression of RSK3 (RPS6KA2) supports cell proliferation and attenuates apoptosis upon PI3K/mTOR inhibition in breast cancer, partly through upregulation of protein translation. MEK or RSK inhibitors can overcome this resistance, placing RSK3 in the RAS-MAPK pathway as a parallel survival route to PI3K signaling. Overexpression in breast cancer cell lines, in vitro proliferation/apoptosis assays, in vivo xenograft models, pharmacological inhibition of MEK and RSK The Journal of clinical investigation High 23635776
2016 RSK3 is required for concentric cardiac myocyte hypertrophy downstream of ERK1/2 signaling in an activated RAF1 (Noonan syndrome) mouse model. RSK3 knockout prevents RAF1(L613V)-dependent concentric myocyte growth and attenuates cardiac hypertrophy, placing RSK3 as an ERK1/2 effector in pathological cardiac remodeling. RSK3 knockout mice crossed with Raf1(L613V) knock-in mice; cardiac morphometry; immunohistochemistry Journal of molecular and cellular cardiology High 26940993
2020 RSK3 interacts with RIP3 (receptor-interacting protein 3) as shown by co-immunoprecipitation, and acts as an upstream regulator of RIP3 phosphorylation during oxygen-glucose deprivation-induced necroptosis in retinal ganglion cells. RSK inhibition (LJH685) or RSK3 siRNA downregulated RIP3 phosphorylation; RIP3 overexpression did not affect RSK3 expression, establishing a directional RSK3→RIP3 regulatory relationship. Co-immunoprecipitation, siRNA knockdown, RSK inhibitor (LJH685), Western blot for pRIP3, computer simulation, in vivo intraocular pressure model Journal of anatomy Medium 32162697
2020 RSK3 phosphorylates ribosomal protein S6 (rpS6) in cartilage stem/progenitor cells (CSPC) to promote their proliferation. RSK3 expression positively correlates with cartilage repair capacity across mouse strains and RSK3-deficient mice show aggravated cartilage damage in OA models. RSK3 knockout mice, chemical enhancement of RSK3 expression, CSPC proliferation assays, transcriptional profiling, in vivo OA model Theranostics Medium 32550912
2020 ERK1/2 and ERK5 kinases phosphorylate and activate RSK3 (RPS6KA2) downstream of EGFR-MEK1/2/5 signaling, leading to enrichment of activated RSK3 that promotes resistance to BET inhibitors (JQ1) in cancer cells. Western blot for RSK3 phosphorylation, MEK/ERK inhibitors, siRNA knockdown of JunD/RSK3, pharmacological rescue experiments Nature communications Medium 31937753
2021 RSK3 binds IκBα as a novel protein-protein interaction partner, identified by kinase library screen and cell-based distribution assay. Active RSK3 phosphorylates IκBα, and a small-molecule inhibitor of the RSK3/IκBα complex reduces breast cancer cell proliferation and increases apoptosis. Kinase library screen, mammalian two-hybrid (MTH) assay, cell-based distribution assay, cell proliferation/colony formation assay, FACS apoptosis assay Cancers Medium 34198590
2022 RSK3 promotes cell survival in TNBC by phosphorylating BAD at Ser112. MYSM1 overexpression leads to RSK3 inactivation and decreased BAD phosphorylation, increasing cisplatin-induced apoptosis. This places RSK3 upstream of the BAD pro-survival pathway in TNBC. Overexpression/knockdown of MYSM1 in TNBC cell lines, Western blot for pBAD(Ser112), apoptosis assays, cisplatin treatment Cell death discovery Medium 35217648
2023 BET inhibition in SCLC leads to RSK3 upregulation, which promotes cell survival by activating the TSC2-mTOR-p70S6K1-BAD cascade. mTOR inhibition blocks this protective RSK3 signaling and augments BET inhibitor-induced apoptosis in vitro and in vivo. Drug combination screens, xenograft models, Western blot for pathway components (TSC2, mTOR, p70S6K1, BAD), apoptosis assays JCI insight Medium 36883564
2023 RSK3 expression is suppressed by TGFβ in a SMAD3-dependent manner, and constitutive RSK3 expression rescues SMAD3-induced senescence in primary human mammary epithelial cells. RSK3 inhibits the NF-κB pathway by decreasing proteasome-mediated IκBα degradation, thereby switching cell fate from TGFβ-induced senescence to malignant EMT progression. Retroviral transduction, kinase library screen, FLAG-IP coupled to mass spectrometry proteomics, proteasome activity assays, Western blot, immunofluorescence, RNA microarray/GSEA, murine intraductal xenografts Journal of experimental & clinical cancer research : CR High 38008756
2025 RPS6KA2 interacts with PCSK9 within the cytoplasmic compartment of colorectal cancer cells and suppresses PCSK9 and MAPK signaling pathway. RPS6KA2 inhibition (BI-D1780) increases PCSK9 and MAPK pathway protein expression, while MAPK inhibitors/stimulators do not affect RPS6KA2 or PCSK9 expression, placing RPS6KA2 upstream of PCSK9-MAPK in CRC. Co-immunoprecipitation/interaction assay, RPS6KA2 inhibitor (BI-D1780), MAPK modulation, Western blot, in vivo tumor growth/metastasis assays Cancer treatment and research communications Medium 40112524
2025 RPS6KA2 inhibits autophagy by modulating the PI3K-AKT-mTOR signaling pathway in ovarian cancer cells, thereby increasing sensitivity to cisplatin. RPS6KA2 also facilitates ferroptosis. miR-512-3p negatively regulates RPS6KA2, driving cisplatin resistance through its suppression. Western blot for PI3K-AKT-mTOR components, autophagy flux assays, autophagosome visualization, ferroptosis parameters (iron content, GSH, ROS, mitochondrial membrane potential), in vivo xenograft experiments Oncology research Medium 41502518

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation. Molecular and cellular biology 125 7623830
2013 RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. The Journal of clinical investigation 112 23635776
2006 RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer. Oncogene 94 16878154
1987 Cloning and sequencing of the HU-2 gene of Escherichia coli. Molecular & general genetics : MGG 79 3312963
2008 ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocrine-related cancer 72 18824559
1980 Complete amino-acid sequences of DNA-binding proteins HU-1 and HU-2 from Escherichia coli. European journal of biochemistry 59 6987059
2010 Genetic variation in RPS6KA1, RPS6KA2, RPS6KB1, RPS6KB2, and PDK1 and risk of colon or rectal cancer. Mutation research 46 21035469
2020 RSK3 mediates necroptosis by regulating phosphorylation of RIP3 in rat retinal ganglion cells. Journal of anatomy 38 32162697
2013 Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer. Neoplasia (New York, N.Y.) 35 24403857
2020 Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance. Nature communications 27 31937753
1988 Genetic characterization of the gene hupA encoding the HU-2 protein of Escherichia coli. Gene 24 3069589
2023 mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer. JCI insight 18 36883564
2015 RSK3: A regulator of pathological cardiac remodeling. IUBMB life 17 25988524
1988 Temporal and constitutive expression of homeobox-2 gene (Hu-2), human heat shock gene (hsp-70), and oncogenes C-sis and N-myc in early human trophoblast. American journal of obstetrics and gynecology 15 2461079
2022 MYSM1 induces apoptosis and sensitizes TNBC cells to cisplatin via RSK3-phospho-BAD pathway. Cell death discovery 14 35217648
2023 ncRNAs mediated RPS6KA2 inhibits ovarian cancer proliferation via p38/MAPK signaling pathway. Frontiers in oncology 12 36741009
2021 A Novel Protein-Protein Interaction between RSK3 and IκBα and a New Binding Inhibitor That Suppresses Breast Cancer Tumorigenesis. Cancers 12 34198590
2020 RSK-3 promotes cartilage regeneration via interacting with rpS6 in cartilage stem/progenitor cells. Theranostics 10 32550912
1992 Amino acid substitution in the C-terminal arm domain of HU-2 results in an enhanced affinity for DNA. Gene 8 1427084
2016 RSK3 is required for concentric myocyte hypertrophy in an activated Raf1 model for Noonan syndrome. Journal of molecular and cellular cardiology 7 26940993
2023 RSK3 switches cell fate: from stress-induced senescence to malignant progression. Journal of experimental & clinical cancer research : CR 6 38008756
1999 The mouse Rsk3 gene maps to the Leh66 elements carrying the t-complex responder Tcr. Mammalian genome : official journal of the International Mammalian Genome Society 5 10430666
2023 Rps6ka2 enhances iMSC chondrogenic differentiation to attenuate knee osteoarthritis through articular cartilage regeneration in mice. Biochemical and biophysical research communications 4 37119767
2022 A Cytological Atlas of the Human Liver Proteome from PROTEOMESKY-LIVERHu 2.0, a Publicly Available Database. Journal of proteome research 2 35820117
2025 Ezetimibe mediated RPS6KA2 inhibits colorectal cancer proliferation via PCSK9/MAPK signaling pathway. Cancer treatment and research communications 1 40112524
2025 ETV1 orchestrates a self-reinforcing ERK1/2-RSK3 signaling loop to drive atrial fibrillation pathogenesis: implications for targeted therapy. Scientific reports 0 41345483
2025 Endothelial-specific genes TMTC1, RPS6KA2, and F8 are downregulated in hypertrophic cardiomyopathy. European journal of medical research 0 41392291
2025 miR-512-3p/RPS6KA2 Axis Regulates Cisplatin Resistance in Ovarian Cancer via Autophagy and Ferroptosis. Oncology research 0 41502518

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