Affinage

RASSF6

Ras association domain-containing protein 6 · UniProt Q6ZTQ3

Length
369 aa
Mass
43.4 kDa
Annotated
2026-06-10
30 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASSF6 is a RAS-effector tumor suppressor that couples activated RAS to apoptosis and cell cycle arrest, with loss of RASSF6 enhancing tumorigenic and invasive phenotypes across multiple cancer types (PMID:17404571, PMID:34652874). It operates at the interface of the Hippo and p53 pathways: RASSF6 binds the Hippo kinase MST2 and inhibits its activity, and upon MST2 activation is released to trigger WW45-dependent apoptosis, defining an apoptotic branch parallel to canonical Hippo signaling (PMID:19797269); it also drives MST1/2 and LATS1 phosphorylation to repress the effector YAP, and YAP repression mediates RASSF6's downregulation of Bcl-xL and induction of mitochondrial apoptosis (PMID:29964010, PMID:31807003). In parallel, RASSF6 binds MDM2 and promotes its ubiquitination, blocking MDM2-mediated p53 degradation to stabilize p53 and impose G1/S arrest, and is required for UV- and VP-16-induced apoptosis, DNA repair, and ploidy control (PMID:24003224, PMID:34652874). Following DNA damage, CDK9-mediated phosphorylation of BAF53 drives nuclear accumulation of RASSF6, which binds BAF53 and bridges its association with BAF60a and p53 to potentiate p53 target-gene transcription (PMID:34898277). In p53-negative contexts RASSF6 retains tumor-suppressor output through a pRb axis, enhancing pRb–phosphatase and pRb–E2F1 interactions and suppressing BMI1 to elevate P16INK4A and P14ARF (PMID:29891515). RASSF6 additionally activates JNK signaling to suppress Mcl-1 and sensitize cells to apoptosis and sorafenib (PMID:24626183, PMID:29864454). Its activity is antagonized by BCL-XL, which binds RASSF6 and blocks the RASSF6–MDM2 interaction (PMID:29193479), and its expression is repressed by oncogenic microRNAs including miR-181a-5p and miR-496 (PMID:28043911, PMID:31273789). RASSF6 localizes to renal epithelial apical membranes and engages cell-junction scaffolds via a C-terminal PDZ-binding motif that binds the PDZ domains of MAGI-1 (PMID:22577168).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2007 Medium

    Established RASSF6 as a RAS-association-domain effector that links activated RAS to apoptosis, raising the question of whether it acts as a tumor suppressor.

    Evidence Exogenous expression and suppression in lung tumor cell lines with cell death assays

    PMID:17404571

    Open questions at the time
    • Downstream apoptotic effectors not defined
    • RAS-binding to growth-suppression mechanism not connected
    • Single cell-line context
  2. 2009 High

    Placed RASSF6 within Hippo signaling by showing it inhibits MST2 and is released upon MST2 activation to trigger WW45-dependent apoptosis, defining a parallel apoptotic branch.

    Evidence Reciprocal Co-IP, kinase activity assays, and epistasis with WW45

    PMID:19797269

    Open questions at the time
    • How RAS binding releases RASSF6 from MST2 not resolved
    • Connection to downstream YAP not yet tested
    • Endogenous stoichiometry unclear
  3. 2012 Medium

    Identified a junctional scaffolding role through PDZ-binding-motif-dependent MAGI-1 binding and defined RASSF6's epithelial localization.

    Evidence Yeast two-hybrid, Co-IP from rat liver, kidney immunolocalization, HK-2 apoptosis assays

    PMID:22577168

    Open questions at the time
    • Functional consequence of MAGI-1 binding not dissected
    • Link between junctional localization and apoptotic signaling unclear
  4. 2013 High

    Connected RASSF6 to the p53 axis by showing it binds MDM2, promotes MDM2 ubiquitination, and stabilizes p53 to enforce arrest and DNA-damage responses.

    Evidence Co-IP, ubiquitination assays, siRNA knockdown, cell cycle and p53 target gene analysis

    PMID:24003224

    Open questions at the time
    • Whether RASSF6 acts as a direct E3 cofactor not determined
    • Structural basis of MDM2 binding unknown
  5. 2014 Medium

    Defined a RASSF6-JNK arm driving apoptosis and p21-dependent G1 arrest, broadening the tumor-suppressor output beyond p53.

    Evidence Ectopic re-expression/knockdown, JNK inhibitor, cell cycle analysis, xenografts in RCC

    PMID:24626183

    Open questions at the time
    • How RASSF6 activates JNK upstream not defined
    • Crosstalk with Hippo/p53 arms not mapped
  6. 2014 Medium

    Showed RASSF6 re-expression suppresses MAPK/AKT signaling and invasion in BRAF-mutant melanoma, increasing mutant B-Raf–MST1 association.

    Evidence Collagen invasion assay, MAPK/AKT western blot, B-Raf/MST1 Co-IP

    PMID:25482183

    Open questions at the time
    • Direct vs indirect MAPK suppression unresolved
    • Mechanism of B-Raf–MST1 bridging unclear
  7. 2016 Medium

    Established RASSF6 as a target of oncogenic microRNAs, with miR-181a-5p directly repressing it to activate MAPK and drive gastric cancer progression.

    Evidence Luciferase 3'UTR reporter, miRNA mimic/inhibitor with RASSF6 rescue, in vivo assays

    PMID:28043911

    Open questions at the time
    • Whether miRNA repression accounts for tumor RASSF6 loss generally not established
  8. 2018 High

    Revealed a p53-independent tumor-suppressor route via pRb: RASSF6 promotes pRb dephosphorylation, suppresses BMI1, and elevates P16INK4A/P14ARF.

    Evidence Co-IP, western blot, siRNA, flow cytometry in p53-negative cells

    PMID:29891515

    Open questions at the time
    • How RASSF6 enhances pRb-phosphatase interaction mechanistically unknown
    • Relationship between pRb and Hippo arms unclear
  9. 2018 Medium

    Linked RASSF6-JNK signaling to Mcl-1 suppression and sorafenib sensitivity, establishing a RASSF6-JNK-Mcl-1 axis.

    Evidence Stable overexpression, JNK inhibitor, Mcl-1 assays, in vitro/in vivo sorafenib resistance

    PMID:29864454

    Open questions at the time
    • Direct mechanism of Mcl-1 downregulation not defined
  10. 2018 Medium

    Positioned YAP downstream of RASSF6, showing RASSF6 activates MST1/2-LATS1 to repress YAP and that YAP repression mediates Bcl-xL downregulation and mitochondrial apoptosis.

    Evidence Overexpression/depletion, YAP rescue epistasis, western blot, JC-1 staining in breast cancer cells

    PMID:29964010

    Open questions at the time
    • Reconciliation with MST2-inhibitory role from 2009 not addressed
    • Direct LATS1 activation mechanism unclear
  11. 2019 Medium

    Confirmed YAP epistasis in a second cancer type, with YAP silencing abolishing RASSF6 effects on Bcl-xL and apoptosis.

    Evidence OE/siRNA, YAP rescue, JC-1, Annexin V/PI in bladder cancer cells

    PMID:31807003

    Open questions at the time
    • Context dependence of RASSF6-YAP regulation across tissues unmapped
  12. 2019 Medium

    Extended miRNA-mediated silencing to miR-496, which directly represses RASSF6 to activate Wnt signaling in colorectal cancer.

    Evidence Luciferase reporter, miR-496 mimic/inhibitor, RASSF6 siRNA rescue, migration/EMT assays

    PMID:31273789

    Open questions at the time
    • Link between RASSF6 loss and Wnt activation not mechanistically dissected
  13. 2019 Medium

    Reported a context where RASSF6 promotes tumor progression by driving ubiquitination-dependent degradation of TRIM16 in esophageal carcinoma.

    Evidence IHC, OE/KD, ubiquitination assay, xenograft and metastasis models

    PMID:31812473

    Open questions at the time
    • Apparent oncogenic role conflicts with tumor-suppressor findings elsewhere
    • Mechanism of TRIM16 ubiquitin-targeting unclear
  14. 2020 Medium

    Showed UNC119A bridges activated KRAS to RASSF6 and enhances the RASSF6-MDM2 interaction to drive p53-dependent apoptosis, connecting RAS sensing to p53 stabilization.

    Evidence Co-IP, immunofluorescence, RNAi, soft-agar, migration/invasion assays in KRAS-mutant cells

    PMID:32554467

    Open questions at the time
    • Structural basis of the KRAS-UNC119A-RASSF6 assembly unknown
  15. 2021 High

    Dissected the DNA-damage-triggered nuclear program, showing CDK9-phosphorylated BAF53 drives RASSF6 nuclear accumulation and that RASSF6 bridges BAF53-BAF60a-p53 to promote p53 target transcription.

    Evidence Fractionation, NLS/NES mapping, Co-IP, CDK9 inhibitor, BAF53/BAF60a siRNA, p53 target and apoptosis assays

    PMID:34898277

    Open questions at the time
    • Direct chromatin recruitment to p53 target promoters not shown
    • Generality across damage types unclear
  16. 2021 High

    Provided in vivo genetic confirmation that Rassf6 is required for UV-induced p53 responses, DNA repair, and senescence and restrains KRAS-driven transformation and skin inflammation.

    Evidence CRISPR/Cas9 knockout mice and MEFs, RNA-seq, soft-agar, DMBA-induced inflammation

    PMID:34652874

    Open questions at the time
    • Tissue-specific contributions not separated
    • Enhanced NF-kB signaling mechanism not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RASSF6 reconciles its dual reported roles—tumor suppressor (MST2/p53/pRb/JNK) versus context-specific oncogenic TRIM16 degradation—and what determines its choice between Hippo, p53, and JNK outputs remains unresolved.
  • No structural model of RASSF6 multi-partner assemblies
  • Determinants of context-dependent output unknown
  • Direct biochemical activity (E3 cofactor vs scaffold) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Partners
BAF53BCL2L1KRASMAGI1MDM2MST2SMARCD1UNC119

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 RASSF6 possesses a Ras Association domain and binds activated Ras, promoting apoptosis and synergizing with activated K-Ras to induce cell death; suppression of RASSF6 enhanced the tumorigenic phenotype of a human lung tumor cell line. Exogenous expression, suppression experiments in tumor cell lines, cell death assays Oncogene Medium 17404571
2009 RASSF6 binds MST2 (mammalian Hippo kinase homolog) and inhibits MST2 kinase activity, antagonizing Hippo signaling; upon MST2 activation, RASSF6 is released and causes apoptosis in a WW45 (mammalian Salvador homolog)-dependent manner, defining a RASSF6-mediated apoptotic pathway parallel to the canonical Hippo pathway. Co-immunoprecipitation, kinase activity assays, epistasis analysis with WW45 Science signaling High 19797269
2012 RASSF6 binds PDZ domains of MAGI-1 through its C-terminal PDZ-binding motif and co-immunoprecipitates with MAGI-1 from rat liver; RASSF6 is localized in normal kidney glomerulus and on apical membranes of renal proximal tubular epithelial cells, and is involved in sorbitol-induced apoptosis together with the Hippo pathway in HK-2 cells. Yeast two-hybrid screening (original identification), co-immunoprecipitation from rat liver, immunolocalization in kidney, functional apoptosis assays in HK-2 cells Journal of biochemistry Medium 22577168
2013 RASSF6 binds MDM2 and facilitates its ubiquitination, thereby blocking MDM2-mediated p53 degradation and stabilizing p53; RASSF6 overexpression induces G1/S arrest in p53-positive cells, and its depletion prevents UV- and VP-16-induced apoptosis and G1/S arrest, delays DNA repair, and increases polyploid cells. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, cell cycle analysis, p53 target gene expression The Journal of biological chemistry High 24003224
2013 RASSF6 mRNA in adipocytes is downregulated by conditioned medium from activated macrophages, and decreased RASSF6 expression upregulates CD44 and HMGA2 mRNA expression in adipocytes. Gene expression profiling in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages, in vivo correlation with macrophage number PloS one Low 23626755
2014 RASSF6 activates JNK signaling to promote apoptosis and p21(Cip1/Waf1)-dependent G1 cell cycle arrest in clear cell renal cell carcinoma cells; JNK inhibitor SP600125 blocked RASSF6-mediated apoptosis sensitization. Ectopic re-expression and siRNA knockdown, JNK inhibitor treatment, cell cycle analysis, tumor xenograft models Cell cycle (Georgetown, Tex.) Medium 24626183
2014 RASSF6 re-expression in metastatic melanoma cells with B-Raf(V600E) inhibited invasion through collagen, suppressed MAPK pathway activation and AKT, and increased association of mutant B-Raf with MST1. Invasion assay through collagen, western blot for MAPK/AKT, co-immunoprecipitation of B-Raf and MST1 Epigenetics Medium 25482183
2016 miR-181a-5p directly represses RASSF6 expression and thereby activates the MAPK signaling pathway, promoting gastric cancer cell proliferation, invasion, and EMT; overexpression or silencing of RASSF6 partially reverses the oncogenic effects of miR-181a-5p. Luciferase reporter assay for direct miR-181a-5p binding to RASSF6 3'UTR, miRNA mimic/inhibitor with rescue by RASSF6 OE/KD, in vitro and in vivo assays Cancer letters Medium 28043911
2016 RASSF6 overexpression in HCC cells suppresses FAK phosphorylation and decreases MMP-2 and MMP-9 expression, inhibiting invasion and migration. Overexpression in HepG2 cells, western blot for p-FAK, MMP-2, MMP-9, invasion assays, xenograft model Oncology research Low 27983932
2017 BCL-XL directly interacts with RASSF6, inhibits the interaction between RASSF6 and MDM2, and suppresses p53 expression, thereby antagonizing RASSF6-mediated apoptosis. Co-immunoprecipitation, p53 expression assays, apoptosis assays with BCL-XL manipulation Genes to cells : devoted to molecular & cellular mechanisms Medium 29193479
2018 RASSF6 mediates cell cycle arrest and apoptosis via pRb independent of p53: RASSF6 enhances the interaction between pRb and protein phosphatase, suppresses BMI1 to increase P16INK4A and P14ARF expression, increases unphosphorylated pRb, augments pRb-E2F1 interaction, and induces TP73 target genes in a p53-negative background. Co-immunoprecipitation, western blot, siRNA knockdown, flow cytometry cell cycle analysis in p53-negative cells Molecular and cellular biology High 29891515
2018 RASSF6 activates the JNK signaling pathway, which contributes to Mcl-1 inhibition; pharmacological JNK pathway suppression partially restores Mcl-1 expression and sorafenib resistance, establishing a RASSF6-JNK-Mcl-1 axis. Stable RASSF6 overexpression in RCC cell lines, JNK inhibitor treatment, Mcl-1 expression assays, in vitro and in vivo sorafenib resistance assays Cancer letters Medium 29864454
2018 RASSF6 activates Hippo signaling by upregulating MST1/2 and LATS1 phosphorylation, represses YAP, and YAP repression mediates RASSF6's effects on Bcl-xL, apoptosis (cleaved caspase-3, cytochrome c), and mitochondrial membrane potential in breast cancer cells. Overexpression/depletion of RASSF6, YAP rescue experiments, western blot, JC-1 staining, flow cytometry Biochemical and biophysical research communications Medium 29964010
2019 miR-496 directly binds RASSF6 and represses its expression, activating Wnt signaling to promote CRC cell migration and EMT; this effect was validated by luciferase reporter assay and RASSF6 siRNA rescue experiments. Luciferase reporter assay, miR-496 mimic/inhibitor, RASSF6 siRNA rescue, migration and EMT assays Journal of cellular physiology Medium 31273789
2019 RASSF6 overexpression in bladder cancer cells downregulates YAP (Hippo pathway effector) and Bcl-xL; YAP silencing abolishes the effects of RASSF6 on Bcl-xL expression, doxorubicin-induced apoptosis, and mitochondrial membrane potential, placing YAP downstream of RASSF6. Overexpression/siRNA knockdown, YAP rescue/epistasis, JC-1 staining, western blot, AnnexinV/PI apoptosis assay OncoTargets and therapy Medium 31807003
2019 RASSF6 negatively regulates TRIM16 by promoting its ubiquitination-dependent degradation in esophageal squamous cell carcinoma cells, thereby activating cell cycle and EMT-associated pathways and promoting ESCC proliferation, migration, and invasion. IHC, OE/KD in ESCC cells, ubiquitination assay, in vivo xenograft and metastasis model Journal of genetics and genomics Medium 31812473
2020 UNC119A (a chaperone of myristoylated proteins) interacts with activated KRAS, promotes KRAS binding to RASSF6, and enhances the RASSF6-MDM2 interaction, driving p53-dependent apoptosis; UNC119A silencing promoted colony formation, migration, and invasion in KRAS-mutated cells. Immunoprecipitation, immunofluorescence, quantitative RT-PCR, RNAi gene silencing, soft-agar colony formation, migration and invasion assays The Journal of biological chemistry Medium 32554467
2021 DNA damage triggers nuclear accumulation of RASSF6 via CDK9-mediated phosphorylation of BAF53; RASSF6 directly binds BAF53 (SWI/SNF complex component), the interaction is enhanced by CDK9, and RASSF6 augments BAF53-BAF60a interaction and their binding to p53, thereby promoting p53 target gene transcription and apoptosis; BAF53 or BAF60a silencing attenuates these effects. Nuclear/cytoplasmic fractionation, identification of nuclear localization and export signals, Co-immunoprecipitation, CDK9 inhibitor treatment, siRNA knockdown of BAF53/BAF60a, p53 target gene expression assays, apoptosis assays Molecular and cellular biology High 34898277
2021 Rassf6 knockout MEFs (generated by CRISPR/Cas9) show resistance to UV-induced apoptosis/cell cycle arrest and senescence, compromised p53-target gene expression, delayed DNA repair, and enhanced NF-κB signaling; KRAS active mutant promotes colony formation of Rassf6-null MEFs but not wild-type MEFs; Rassf6 knockout mice show enhanced skin inflammation upon DMBA treatment. CRISPR/Cas9 knockout mice, MEF cultures, UV treatment, RNA-seq, p53 target gene expression, soft-agar colony formation, in vivo DMBA-induced inflammation Genes to cells : devoted to molecular & cellular mechanisms High 34652874

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 RASSF6 is a novel member of the RASSF family of tumor suppressors. Oncogene 114 17404571
2009 The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias. Molecular cancer 91 19570220
2016 miR-181a-5p promotes the progression of gastric cancer via RASSF6-mediated MAPK signalling activation. Cancer letters 90 28043911
2009 Hippo pathway-dependent and -independent roles of RASSF6. Science signaling 84 19797269
2012 The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma. Molecular cancer 64 22695170
2014 RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells. Epigenetics 37 25482183
2013 The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle via MDM2 protein and p53 protein. The Journal of biological chemistry 35 24003224
2019 MiR-496 promotes migration and epithelial-mesenchymal transition by targeting RASSF6 in colorectal cancer. Journal of cellular physiology 30 31273789
2016 Decreased level of RASSF6 in sporadic colorectal cancer and its anti-tumor effects both in vitro and in vivo. Oncotarget 19 27009808
2015 RASSF6; the Putative Tumor Suppressor of the RASSF Family. Cancers 19 26690221
2014 RASSF6 promotes p21(Cip1/Waf1)-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma. Cell cycle (Georgetown, Tex.) 19 24626183
2021 Down-regulation of circITCH promotes osteosarcoma development and resistance to doxorubicin via the miR-524/RASSF6 axis. The journal of gene medicine 18 34151476
2018 The RASSF6 Tumor Suppressor Protein Regulates Apoptosis and Cell Cycle Progression via Retinoblastoma Protein. Molecular and cellular biology 18 29891515
2012 Expression of RASSF6 in kidney and the implication of RASSF6 and the Hippo pathway in the sorbitol-induced apoptosis in renal proximal tubular epithelial cells. Journal of biochemistry 18 22577168
2018 Downregulation of RASSF6 promotes breast cancer growth and chemoresistance through regulation of Hippo signaling. Biochemical and biophysical research communications 17 29964010
2014 Downregulation of Ras association domain family member 6 (RASSF6) underlies the treatment resistance of highly metastatic nasopharyngeal carcinoma cells. PloS one 14 25028967
2013 RASSF6 expression in adipocytes is down-regulated by interaction with macrophages. PloS one 14 23626755
2018 RASSF6-mediated inhibition of Mcl-1 through JNK activation improves the anti-tumor effects of sorafenib in renal cell carcinoma. Cancer letters 13 29864454
2019 RASSF6 Is Downregulated In Human Bladder Cancers And Regulates Doxorubicin Sensitivity And Mitochondrial Membrane Potential Via The Hippo Signaling Pathway. OncoTargets and therapy 12 31807003
2020 lncRNA TUSC7 inhibits osteosarcoma progression through the miR‑181a/RASSF6 axis. International journal of molecular medicine 11 33416181
2019 RASSF6-TRIM16 axis promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma. Journal of genetics and genomics = Yi chuan xue bao 10 31812473
2019 Residual methylation of tumor suppressor gene promoters, RASSF6 and RASSF10, as novel biomarkers for minimal residual disease detection in adult acute lymphoblastic leukemia. Annals of hematology 9 31486880
2017 BCL-XL binds and antagonizes RASSF6 tumor suppressor to suppress p53 expression. Genes to cells : devoted to molecular & cellular mechanisms 9 29193479
2016 Overexpression of RAS-Association Domain Family 6 (RASSF6) Inhibits Proliferation and Tumorigenesis in Hepatocellular Carcinoma Cells. Oncology research 8 27983932
2021 DNA Damage Triggers the Nuclear Accumulation of RASSF6 Tumor Suppressor Protein via CDK9 and BAF53 To Regulate p53 Target Gene Transcription. Molecular and cellular biology 4 34898277
2020 The RAS-interacting chaperone UNC119 drives the RASSF6-MDM2-p53 axis and antagonizes RAS-mediated malignant transformation. The Journal of biological chemistry 4 32554467
2021 Kindlin-3 and RASSF6 are probable biomarkers for predicting metastasis in cutaneous melanoma. Polish journal of pathology : official journal of the Polish Society of Pathologists 3 35048636
2025 Induction of miR-224 by Reactive Oxygen Species Regulates RASSF6 and Thus Modulates Malignant Behaviors and Chemosensitivity in Esophageal Squamous Cell Carcinoma. Journal of biochemical and molecular toxicology 2 40067291
2025 Apoptotic role of RASSF6 in regulating PRV-infected porcine alveolar macrophages. Open veterinary journal 0 41630709
2021 Characterization of mouse embryonic fibroblasts derived from Rassf6 knockout mice shows the implication of Rassf6 in the regulation of NF-κB signaling. Genes to cells : devoted to molecular & cellular mechanisms 0 34652874

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