Affinage

RASSF2

Ras association domain-containing protein 2 · UniProt P50749

Length
326 aa
Mass
37.8 kDa
Annotated
2026-06-10
26 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASSF2 is a K-Ras-specific effector and tumor suppressor that links activated Ras to proapoptotic and growth-suppressive programs while shuttling between nucleus and cytoplasm (PMID:12732644, PMID:17891178). It binds K-Ras directly in a GTP-dependent manner through its Ras-association domain, with this interaction required for its full proapoptotic activity, and loss of RASSF2 enhances K-Ras-driven transformation (PMID:12732644, PMID:18294275, PMID:16012945). RASSF2 engages the proapoptotic Hippo kinases MST1 and MST2 via its SARAH domain, activating MST kinase activity and protecting MST2 from proteolytic degradation; reciprocally MST1 stabilizes RASSF2, and the MST-interaction domain is required for RASSF2-induced apoptosis (PMID:19525978, PMID:19962960, PMID:20920251). Its localization is tightly controlled: a bipartite NLS drives nuclear accumulation needed for growth suppression, while ERK2-mediated phosphorylation licenses CRM-1-dependent nuclear export through a C-terminal NES, and import-defective RASSF2 fails to induce G1/S arrest or apoptosis (PMID:17891178, PMID:19555684). In the nucleus and cytoplasm RASSF2 acts as a scaffold for additional apoptotic and signaling factors, forming a K-Ras-regulated complex with PAR-4 to promote PAR-4 nuclear translocation and apoptosis (PMID:20368356), and restraining oncogenic signaling by stabilizing PTEN to suppress PI3K/AKT and by binding IKKα/β to inhibit NF-κB during osteoclast and osteoblast differentiation (PMID:42095894, PMID:22227519). Beyond canonical Hippo signaling, RASSF2 associates with Rac GTPase regulators including DOCK2 to sustain Rac activation and suppresses t(8;21) AML (PMID:32029705). RASSF2 is recurrently silenced in cancer through promoter CpG-associated SETDB1-driven H3K9me3 and is targeted by miR-7 and the miR-200 family, integrating it into tumor-suppressive networks across multiple tissues (PMID:42095894, PMID:27901488, PMID:31565080).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    Established RASSF2 as a direct, GTP-dependent K-Ras effector, defining the molecular basis for its placement in Ras signaling rather than a generic Ras-association protein.

    Evidence Direct pulldown binding assays with GTP-dependence and cell-based apoptosis/cell cycle assays

    PMID:12732644

    Open questions at the time
    • Did not resolve downstream effectors mediating apoptosis
    • Structural basis of K-Ras specificity over H-Ras not defined
  2. 2005 Medium

    Positioned RASSF2 functionally downstream of K-Ras as a negative regulator of transformation, showing its loss cooperates with oncogenic Ras.

    Evidence Colony formation, flow cytometry, and functional complementation in colorectal cancer cells

    PMID:16012945

    Open questions at the time
    • Molecular mechanism of transformation suppression not defined
    • Single-lab cell-based evidence
  3. 2008 Medium

    Demonstrated that the Ras-association domain is required for RASSF2 proapoptotic function, tying its apoptotic role to Ras binding.

    Evidence Ras-association domain deletion mutagenesis with apoptosis assay in OSCC cells

    PMID:18294275

    Open questions at the time
    • Does not identify the apoptotic effector engaged downstream of Ras binding
    • Single cell type
  4. 2007 High

    Identified a functional bipartite NLS and showed nuclear localization is required for tumor-suppressor activity, establishing RASSF2 as a localization-dependent suppressor.

    Evidence NLS mutagenesis with immunofluorescence and in vitro/in vivo growth suppression assays

    PMID:17891178

    Open questions at the time
    • Nuclear targets of RASSF2 not identified
    • Mechanism coupling nuclear residence to growth suppression unresolved
  5. 2009 High

    Defined the RASSF2-MST1/2 axis: RASSF2 binds MST kinases via its SARAH domain, activates them, and protects MST2 from degradation, while MST1 reciprocally stabilizes RASSF2.

    Evidence Endogenous Co-IP, knockdown, kinase activity assays, and Mst1 knockout mice

    PMID:19525978 PMID:19962960

    Open questions at the time
    • MST-independent JNK/apoptosis branch mechanism not fully resolved
    • Identity of the co-immunoprecipitating kinase phosphorylating RASSF2 not definitively established
  6. 2009 High

    Established that ERK2 phosphorylation controls CRM-1-dependent nuclear export through a defined C-terminal NES, coupling MAPK signaling to RASSF2 subcellular distribution and function.

    Evidence NES mutagenesis, leptomycin B, CRM-1 interaction, MAPK inhibition, in vitro phosphorylation, and cell cycle/apoptosis assays

    PMID:19555684

    Open questions at the time
    • Phosphosite(s) on RASSF2 targeted by ERK2 not mapped
    • How nucleocytoplasmic shuttling integrates with MST/PAR-4 functions unclear
  7. 2010 High

    Showed RASSF2 scaffolds PAR-4 and drives its nuclear translocation in a K-Ras-regulated manner, providing a mechanism for PAR-4-dependent apoptosis.

    Evidence Endogenous Co-IP, subcellular fractionation, and apoptosis assays in prostate tumor cells

    PMID:20368356

    Open questions at the time
    • How K-Ras regulation switches the RASSF2-PAR-4 interaction is not defined
    • Relationship to MST-dependent apoptosis not integrated
  8. 2010 Medium

    Confirmed the MST-interaction domain is functionally required for RASSF2-induced apoptosis in a distinct cancer type, generalizing the MST-dependence of its apoptotic activity.

    Evidence MST-interaction domain deletion with apoptosis assay in thyroid cancer cells

    PMID:20920251

    Open questions at the time
    • Does not separate MST binding from MST activation
    • Single-lab evidence
  9. 2012 Medium

    Linked RASSF2 loss to AKT activation and validated endogenous RASSF2-K-Ras complexes in lung cancer, connecting RASSF2 to PI3K/AKT signaling.

    Evidence RNAi knockdown, endogenous Co-IP, AKT phosphorylation, and growth/invasion assays

    PMID:22693671

    Open questions at the time
    • Mechanism linking RASSF2 to AKT not established at this stage
    • Single-lab readouts
  10. 2012 High

    Revealed an in vivo physiological role in bone remodeling and hematopoiesis and a mechanism whereby RASSF2 binds and inhibits IKKα/β to restrain NF-κB during differentiation.

    Evidence Rassf2 knockout mice, in vitro differentiation, RASSF2-IKK Co-IP, IKK kinase assay, and dominant-negative rescue

    PMID:22227519

    Open questions at the time
    • How NF-κB suppression relates to RASSF2 apoptotic/Ras functions unclear
    • Structural basis of IKK inhibition not defined
  11. 2016 Medium

    Expanded the RASSF2 interactome to C1QBP and Vimentin in a K-Ras-modulated manner, linking RASSF2/K-Ras to vimentin acetylation.

    Evidence Proteomics/MS pulldown with Co-IP validation and acetylation assay

    PMID:26999212

    Open questions at the time
    • Functional consequence of C1QBP and Vimentin binding not established
    • Mechanism of vimentin acetylation control unresolved
  12. 2017 Medium

    Placed RASSF2 in a miR-7-RASSF2-PAR-4 axis in cancer-associated fibroblasts, showing its repression alters the tumor microenvironment.

    Evidence miRNA gain/loss, co-culture, target validation, and proliferation/migration assays

    PMID:27901488

    Open questions at the time
    • Direct mechanism of PAR-4 secretion control not defined
    • Single-lab co-culture model
  13. 2019 Medium

    Identified the miR-200 family as a direct regulator of RASSF2 mRNA coupling its levels to ERK/MAPK signaling, adding a feedback layer to RASSF2 regulation.

    Evidence miRNA gain/loss, knockdown, and ERK phosphorylation/proliferation readouts in colon cancer cells

    PMID:31565080

    Open questions at the time
    • Direct biochemical target binding not structurally validated
    • Single cell line
  14. 2020 High

    Showed RASSF2 suppresses t(8;21) AML through MST1/2 interaction independent of canonical Hippo signaling and uncovered association with Rac regulators including DOCK2 to sustain Rac activation.

    Evidence AML re-expression models in vitro/in vivo, BioID proximity labeling, Co-IP, and Rac activation assays

    PMID:32029705

    Open questions at the time
    • Direct vs indirect nature of RASSF2-DOCK2 association not resolved
    • How RASSF2 promotes Rac activation mechanistically unclear
  15. 2023 Medium

    Extended RASSF2 function to oxidative stress-induced apoptosis in lens epithelium via AKT Ser473 regulation, showing context-dependent proapoptotic signaling.

    Evidence Overexpression/knockdown, AKT phosphorylation western blots, and mouse model

    PMID:37979829

    Open questions at the time
    • Direction of AKT regulation appears context-specific and is not mechanistically reconciled with tumor-suppressor PTEN/AKT findings
    • Single-lab study
  16. 2026 Medium

    Defined a PTEN-stabilizing mechanism for RASSF2-mediated PI3K/AKT suppression and identified SETDB1-driven H3K9me3 as a transcriptional silencing mechanism in ovarian cancer.

    Evidence ChIP for SETDB1/H3K9me3 at the RASSF2 promoter, RASSF2-PTEN Co-IP, and cycloheximide chase assays

    PMID:42095894

    Open questions at the time
    • Mechanism by which RASSF2 stabilizes PTEN not defined
    • Single-lab evidence
  17. 2026 Medium

    Showed cell-surface nucleolin binds RASSF2 and drives its nuclear translocation to promote endothelial pyroptosis, implicating RASSF2 in vascular inflammation.

    Evidence IP-MS, Co-IP, subcellular fractionation, NCL knockdown, and in vivo atherosclerosis model

    PMID:41895182

    Open questions at the time
    • How nuclear RASSF2 triggers pyroptosis mechanistically is unresolved
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RASSF2 integrates its distinct effector branches (MST/Hippo, PAR-4, IKK/NF-κB, PTEN/AKT, Rac/DOCK2) into a unified, context-dependent program, and whether its apparently opposing roles in apoptosis suppression versus promotion reflect tissue-specific partner availability.
  • No structural model of RASSF2 with its multiple partners
  • No unified framework reconciling tumor-suppressive and proinflammatory/proapoptotic roles across tissues

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 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3
Partners
DOCK2IKBKBKRASMST1MST2NCLPAWRPTEN

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 RASSF2 binds directly to K-Ras in a GTP-dependent manner via the Ras effector domain, but only weakly interacts with H-Ras, establishing it as a K-Ras-specific effector. RASSF2 promotes apoptosis and cell cycle arrest. Direct binding assay (pulldown), GTP-dependence assay, cell-based apoptosis and cell cycle assays The Journal of biological chemistry High 12732644
2005 RASSF2 induces morphological changes and apoptosis when ectopically expressed in colorectal cancer cells, and inactivation of RASSF2 enhances K-Ras-induced oncogenic transformation, placing RASSF2 downstream of K-Ras as a negative regulator of transformation. Colony formation assay, flow cytometry, immunofluorescence microscopy, functional complementation Gastroenterology Medium 16012945
2007 RASSF2 contains a functional bipartite nuclear localization signal (NLS); mutation of the NLS abolishes nuclear localization and significantly diminishes its tumor suppressor (growth suppression) activity, demonstrating that nuclear localization is required for full RASSF2 function. Site-directed mutagenesis of NLS, immunofluorescence localization, in vitro and in vivo growth suppression assays Oncogene High 17891178
2009 RASSF2 associates with the proapoptotic kinases MST1 and MST2 via its SARAH domain, and this interaction is confirmed at endogenous levels. RASSF2 co-immunoprecipitates active MST1/2, is phosphorylated by a co-immunoprecipitating kinase (likely MST1/2), and stabilizes MST2 by protecting it from proteolytic degradation. RASSF2 alone localizes to the nucleus, but co-expression with MST1 or MST2 results in cytoplasmic co-localization. Co-immunoprecipitation (endogenous), immunofluorescence co-localization, stable/transient expression, RASSF2 knockdown, kinase activity assay Oncogene High 19525978
2009 MST1 regulates RASSF2 protein stability: knockdown of MST1 markedly destabilizes RASSF2, and Mst1-deficient mice show reduced Rassf2 protein levels. Conversely, RASSF2 activates MST1 kinase activity through formation of a RASSF2-MST1 complex. RASSF2 also activates JNK signaling and induces apoptosis in an MST1-independent manner. siRNA knockdown, Mst1 knockout mice, kinase activity assay, complex formation (Co-IP), apoptosis assay, JNK pathway assay Biochemical and biophysical research communications High 19962960
2009 RASSF2 shuttles between nucleus and cytoplasm via a CRM-1-dependent nuclear export mechanism. A functional nuclear export signal (NES) resides in amino acids 240–260 (C-terminus); mutation of conserved residues Ile254, Val257, and Leu259 impairs nuclear export and interaction with CRM-1. ERK2 (MAPK) phosphorylates RASSF2 and this phosphorylation is required for nuclear export; inhibition of MAPK pathway blocks RASSF2 export. Nuclear import-defective RASSF2 fails to induce G1/S cell cycle arrest or apoptosis. NES mutagenesis, leptomycin B treatment, CRM-1 interaction assay, MAPK inhibitor treatment, in vitro phosphorylation assay, cell cycle and apoptosis assays Experimental cell research High 19555684
2010 RASSF2 forms a direct and endogenous complex with PAR-4 (prostate apoptosis response protein 4). This interaction is regulated by K-Ras and is essential for the full apoptotic effects of PAR-4. RASSF2 (a primarily nuclear protein) modulates nuclear translocation of PAR-4 from cytoplasm to nucleus in prostate tumor cells, providing a mechanism for PAR-4's biological apoptotic effects. Co-immunoprecipitation (endogenous), subcellular fractionation/localization, functional apoptosis assay Molecular and cellular biology High 20368356
2010 Deletion of the MST interaction domain of RASSF2 significantly reduces RASSF2-induced apoptosis in thyroid cancer cells, establishing that the MST interaction domain is functionally required for RASSF2-mediated apoptosis. Domain deletion mutagenesis, apoptosis assay in thyroid cancer cells Molecular cancer Medium 20920251
2008 A RASSF2 deletion mutant lacking the Ras-association domain, unable to interact with Ras, exhibits less pro-apoptotic activity than the full-length protein, demonstrating that the pro-apoptotic activity of RASSF2 is related to its association with Ras. Deletion mutagenesis, apoptosis assay in OSCC cells Cancer science Medium 18294275
2012 Loss of RASSF2 expression in lung cancer cells correlates with increased levels of activated AKT, indicating RASSF2 modulates Ras/AKT signaling. RASSF2 and K-Ras form an endogenous complex (confirmed by Co-IP), validating RASSF2 as a bona fide K-Ras effector in lung cancer cells. RNAi knockdown, Co-immunoprecipitation (endogenous), AKT phosphorylation assay, cell proliferation/invasion/anchorage-independent growth assays Molecular biology international Medium 22693671
2012 Rassf2 knockout mice develop bone remodeling defects and haematopoietic anomalies. RASSF2 ablation suppresses osteoblastogenesis and promotes osteoclastogenesis in vitro. RASSF2 associates with IKKα and IKKβ and suppresses IKK kinase activity, thereby restraining NF-κB signaling during osteoclast and osteoblast differentiation. Reintroduction of RASSF2 or dominant-negative IKK normalizes differentiation in Rassf2-/- precursors. Knockout mouse model, bone marrow transplantation, in vitro differentiation assay, Co-immunoprecipitation (RASSF2-IKKα/β), IKK kinase activity assay, dominant-negative rescue The EMBO journal High 22227519
2016 Proteomics-based screening identified novel RASSF2 interaction partners including C1QBP and Vimentin. The RASSF2-C1QBP interaction is enhanced by K-Ras, while the RASSF2-Vimentin interaction is reduced by K-Ras. RASSF2/K-Ras regulates the acetylation of Vimentin. Proteomics/MS pulldown, Co-immunoprecipitation validation, acetylation assay Cancers Medium 26999212
2017 RASSF2 is a direct target of miR-7 in cancer-associated fibroblasts. Overexpression of miR-7 down-regulates RASSF2, which reduces PAR-4 secretion from fibroblasts and enhances proliferation and migration of co-cultured cancer cells, placing RASSF2 in a miR-7-RASSF2-PAR-4 signaling axis. miRNA overexpression/inhibition, co-culture assay, bioinformatic target validation, functional proliferation/migration assay Oncotarget Medium 27901488
2020 RASSF2 suppresses t(8;21) AML development, and its function depends on interaction with Hippo kinases MST1 and MST2, but is independent of canonical Hippo pathway signaling. Proximity-based biotin labeling revealed RASSF2 associates with Rac GTPase-related proteins including the guanine nucleotide exchange factor DOCK2. RASSF2 knockdown impairs Rac GTPase activation. Re-expression in AML models (in vitro and in vivo), proximity-based biotin labeling (BioID), Co-immunoprecipitation, Rac GTPase activation assay, MST1/2 interaction studies Blood cancer journal High 32029705
2019 The miR-200 family directly targets RASSF2 mRNA; knockdown of the miR-200 family in HT-29 colon cancer cells increases RASSF2 expression and decreases ERK phosphorylation (MAPK/ERK signaling), while increased miR-200 expression decreases RASSF2 and increases ERK phosphorylation. siRNA knockdown, miRNA gain/loss of function, western blot for ERK phosphorylation, cell proliferation assay Oncology letters Medium 31565080
2023 RASSF2 mediates oxidative stress-induced apoptosis in lens epithelial cells by regulating AKT (Ser473) phosphorylation. Overexpression of RASSF2 promotes apoptosis under oxidative conditions, while knockdown reduces it. EGCG inhibits this pathway by reducing RASSF2 levels, thereby suppressing AKT phosphorylation and apoptosis. Overexpression and siRNA knockdown in lens epithelial cells, western blot for AKT Ser473 phosphorylation, mouse model European journal of pharmacology Medium 37979829
2026 Cell surface nucleolin (NCL) interacts with RASSF2 via its RNA-binding domain, and NCL facilitates nuclear translocation of RASSF2. This nuclear transport of RASSF2 exacerbates endothelial cell pyroptosis and amplifies inflammatory responses in atherosclerosis. Immunoprecipitation-mass spectrometry (IP-MS), Co-immunoprecipitation, subcellular fractionation, NCL knockdown, in vivo atherosclerosis model Atherosclerosis Medium 41895182
2026 SETDB1 catalyzes H3K9me3 histone methylation at the RASSF2 promoter, transcriptionally repressing RASSF2 in ovarian cancer. RASSF2 stabilizes PTEN protein (demonstrated by Co-IP and cycloheximide chase assays) to inhibit PI3K/AKT pathway activation. Chromatin immunoprecipitation (ChIP) for SETDB1 and H3K9me3 at RASSF2 promoter, Co-immunoprecipitation (RASSF2-PTEN), cycloheximide chase assay, in vitro and in vivo overexpression/knockdown Molecular genetics and genomics Medium 42095894

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. The Journal of biological chemistry 151 12732644
2005 The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Gastroenterology 114 16012945
2009 RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene 70 19525978
2005 RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer. British journal of cancer 62 16265349
2010 Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences. Molecular cancer 49 20920251
2017 Cancer-associated fibroblasts promote cancer cell growth through a miR-7-RASSF2-PAR-4 axis in the tumor microenvironment. Oncotarget 47 27901488
2009 Role of the tumor suppressor RASSF2 in regulation of MST1 kinase activity. Biochemical and biophysical research communications 47 19962960
2019 The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2. Oncology letters 44 31565080
2007 Epigenetic regulation of the ras effector/tumour suppressor RASSF2 in breast and lung cancer. Oncogene 43 17891178
2008 Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma. Cancer science 42 18294275
2012 Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. The EMBO journal 36 22227519
2013 RASSF2 hypermethylation is present and related to shorter survival in squamous cervical cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 29 23542458
2010 The Ras effector RASSF2 controls the PAR-4 tumor suppressor. Molecular and cellular biology 27 20368356
2007 Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers. International journal of oncology 27 17549418
2016 Comparative Modeling, Molecular Docking, and Revealing of Potential Binding Pockets of RASSF2; a Candidate Cancer Gene. Interdisciplinary sciences, computational life sciences 20 26782783
2012 Loss of RASSF2 Enhances Tumorigencity of Lung Cancer Cells and Confers Resistance to Chemotherapy. Molecular biology international 18 22693671
2020 The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling. Blood cancer journal 14 32029705
2009 Extracellular signal-regulated kinase 2 (ERK-2) mediated phosphorylation regulates nucleo-cytoplasmic shuttling and cell growth control of Ras-associated tumor suppressor protein, RASSF2. Experimental cell research 12 19555684
2016 Proteomics Analysis Reveals Novel RASSF2 Interaction Partners. Cancers 10 26999212
2023 Epigallocatechin gallate delays age-related cataract development via the RASSF2/AKT pathway. European journal of pharmacology 8 37979829
2014 [Detection of RASSF2 and sFRP1 promoter region methylation in sporadic colorectal cancer patients]. Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 4 24519048
2023 Hyperhomocysteinemia may aggravate abdominal aortic aneurysm formation by up-regulating RASSF2. Gene 2 38036076
2019 Association Between RASSF2 Methylation and Gastric Cancer: A PRISMA-Compliant Systematic Review and Meta-Analysis. DNA and cell biology 2 31453724
2026 Cell surface nucleolin promotes endothelial cell pyroptosis in atherosclerosis through RASSF2. Atherosclerosis 0 41895182
2026 RASSF2 promoter hypermethylation determines malignant and microenvironmental features in lung cancer. Genes and immunity 0 42020562
2026 SETDB1 induces H3K9me3 methylation modification of RASSF2 to inhibit PTEN and facilitate ovarian cancer progression. Molecular genetics and genomics : MGG 0 42095894

Missed literature

Know a paper Affinage missed for RASSF2? Flag it for the maintainers and the community.

No submissions yet.