Affinage

RASSF2

Ras association domain-containing protein 2 · UniProt P50749

Length
326 aa
Mass
37.8 kDa
Annotated
2026-04-28
25 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASSF2 is a K-Ras-specific effector and tumor suppressor that integrates Ras signaling with apoptosis, cell cycle control, and NF-κB-dependent differentiation programs. It binds K-Ras in a GTP-dependent manner through its Ras-association (RA) domain and shuttles between cytoplasm and nucleus via a bipartite NLS and an ERK2-phosphorylation-regulated NES, with nuclear localization required for its growth-suppressive and pro-apoptotic functions (PMID:12732644, PMID:17891178, PMID:19555684). In the nucleus, RASSF2 forms endogenous complexes with the Hippo pathway kinases MST1/MST2—stabilizing MST2, activating MST1 kinase activity, and requiring this interaction for full apoptosis induction—and with the tumor suppressor PAR-4, facilitating PAR-4 nuclear translocation to promote apoptosis (PMID:19525978, PMID:19962960, PMID:20368356). RASSF2 also suppresses NF-κB signaling by directly binding and inhibiting IKKα/IKKβ, thereby regulating osteoblast and osteoclast differentiation in vivo, and associates with the Rac GEF DOCK2 to support Rac GTPase activation in hematopoietic cells (PMID:22227519, PMID:32029705).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    The identity of RASSF2 as a Ras effector was unknown; GTP-dependent binding assays established it as a K-Ras-specific interactor that induces apoptosis and cell cycle arrest, framing it as a tumor suppressor downstream of Ras.

    Evidence Direct binding assay demonstrating GTP-dependent K-Ras interaction with selectivity over H-Ras, plus overexpression-based apoptosis/cell cycle readouts

    PMID:12732644

    Open questions at the time
    • No structural basis for K-Ras selectivity
    • Endogenous complex not yet validated
    • Downstream signaling pathway not defined
  2. 2005 Medium

    Whether the RA domain was functionally required for tumor suppression was untested; deletion mutant analysis in colorectal and oral cancer cells showed that the RA domain is necessary for full pro-apoptotic activity, linking Ras binding to the apoptotic mechanism.

    Evidence Colony formation, flow cytometry, and deletion mutant analysis in colorectal and oral squamous cell carcinoma lines

    PMID:16012945 PMID:18294275

    Open questions at the time
    • Mechanism connecting Ras binding to apoptosis execution not identified
    • RA-domain deletion may affect protein folding rather than interaction specifically
  3. 2007 High

    The subcellular site of RASSF2 action was unclear; identification of a functional bipartite NLS and demonstration that its mutation abolishes growth-suppressive activity established nuclear localization as essential for tumor suppressor function.

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

    PMID:17891178

    Open questions at the time
    • Nuclear targets mediating growth suppression not identified
    • Regulation of nuclear import not addressed
  4. 2009 High

    How RASSF2 nucleocytoplasmic shuttling is regulated was unknown; identification of a functional NES (aa 240–260) and demonstration that ERK2 phosphorylation drives CRM-1-dependent nuclear export revealed that the MAPK pathway antagonizes RASSF2 nuclear function.

    Evidence NES mutagenesis, leptomycin B treatment, CRM-1 Co-IP, in vitro ERK2 kinase assay, MAPK inhibitor experiments

    PMID:19555684

    Open questions at the time
    • Specific ERK2 phosphorylation sites not fully mapped
    • Physiological contexts triggering RASSF2 nuclear export not defined
  5. 2009 High

    The effector pathway linking RASSF2 to apoptosis execution was undefined; reciprocal endogenous co-immunoprecipitation and kinase assays showed that RASSF2 forms complexes with MST1/MST2, stabilizes MST2 against degradation, and activates MST1 kinase activity, establishing the Hippo kinase axis as a core RASSF2 effector mechanism.

    Evidence Endogenous reciprocal Co-IP, siRNA knockdown, Mst1-knockout mouse, in vitro kinase activity assay, colocalization microscopy

    PMID:19525978 PMID:19962960

    Open questions at the time
    • Whether RASSF2 activates canonical Hippo (YAP/TAZ) signaling downstream of MST not resolved
    • Structural basis of RASSF2-MST interaction not determined
  6. 2010 High

    Whether RASSF2 cooperates with other tumor suppressors was open; endogenous complex formation with PAR-4 and demonstration that RASSF2 facilitates K-Ras-dependent PAR-4 nuclear translocation identified a second apoptotic effector arm distinct from MST.

    Evidence Endogenous Co-IP, nuclear translocation assay, apoptosis assays with K-Ras modulation in prostate cancer cells

    PMID:20368356

    Open questions at the time
    • Whether MST and PAR-4 arms are redundant or synergistic not tested
    • Direct versus indirect nature of K-Ras regulation of RASSF2-PAR-4 not distinguished
  7. 2010 Medium

    Whether the MST interaction domain is functionally required was not directly tested by domain deletion in the apoptosis context; deletion of the MST-binding region significantly reduced apoptosis induction in thyroid cancer cells, confirming functional dependence.

    Evidence Domain deletion mutagenesis with apoptosis quantification in thyroid cancer cells

    PMID:20920251

    Open questions at the time
    • Domain deletion may disrupt other interactions besides MST
    • Downstream MST substrates mediating the apoptotic signal not identified
  8. 2012 High

    The physiological role of RASSF2 beyond cancer was unknown; Rassf2-knockout mice revealed bone remodeling defects due to NF-κB hyperactivation, and biochemical studies showed RASSF2 directly binds and inhibits IKKα/IKKβ, establishing a non-Hippo effector pathway controlling osteoblast/osteoclast differentiation.

    Evidence Knockout mouse, bone marrow transplantation, in vitro differentiation, IKK activity assay, Co-IP, dominant-negative IKK rescue

    PMID:22227519

    Open questions at the time
    • Whether IKK inhibition contributes to RASSF2 tumor suppressor activity not tested
    • Structural basis of IKK inhibition unknown
  9. 2012 Medium

    Whether RASSF2 modulates canonical Ras effector pathways was unclear; endogenous RASSF2-K-Ras co-immunoprecipitation and knockdown experiments demonstrated that RASSF2 loss increases activated AKT levels, linking RASSF2 to restraint of PI3K-AKT signaling.

    Evidence Endogenous Co-IP, RNAi knockdown with AKT phosphorylation readout in K-Ras-mutant lung cancer cells

    PMID:22693671

    Open questions at the time
    • Mechanism by which RASSF2 suppresses AKT activation not defined
    • Direct versus indirect effect on PI3K pathway not resolved
  10. 2020 High

    Whether RASSF2 engages pathways beyond Hippo and NF-κB was unresolved; BioID proximity labeling in AML cells revealed association with Rac GTPase pathway components including the GEF DOCK2, and RASSF2 knockdown impaired Rac activation, identifying a new signaling axis through which RASSF2 suppresses leukemia.

    Evidence BioID proximity labeling, Co-IP, Rac GTPase activation assay, re-expression in multiple AML models

    PMID:32029705

    Open questions at the time
    • Direct versus adaptor role for RASSF2 in Rac activation not distinguished
    • Whether DOCK2-Rac axis operates in solid tumors not tested
  11. 2026 Medium

    How RASSF2 nuclear import is regulated by extracellular cues was unknown; identification of cell-surface nucleolin as a binding partner that facilitates RASSF2 nuclear transport expanded the import mechanism and linked RASSF2 nuclear accumulation to endothelial pyroptosis in atherosclerosis.

    Evidence IP-mass spectrometry, siRNA knockdown of nucleolin, nuclear fractionation, pyroptosis assays in ApoE-/- mouse model

    PMID:41895182

    Open questions at the time
    • Mechanism by which surface nucleolin accesses cytoplasmic RASSF2 not explained
    • Pyroptosis pathway downstream of nuclear RASSF2 not defined
    • Single lab; independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for K-Ras selectivity, the precise mechanism by which RASSF2 inhibits IKK, and whether the MST, PAR-4, Rac/DOCK2, and NF-κB effector arms are coordinated or context-specific remain unresolved.
  • No crystal or cryo-EM structure of RASSF2 or any of its complexes
  • Integration of MST, PAR-4, IKK, and Rac pathways not tested in a single system
  • In vivo tumor suppressor validation limited to Rassf2-knockout bone phenotype; no tumor model published

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 4 GO:0005829 cytosol 2
Pathway
R-HSA-5357801 Programmed Cell Death 7 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 1
Partners
DOCK2IKBKAIKBKBKRASMST1MST2NCLPAWR

Evidence

Reading pass · 15 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, identifying it as a K-Ras-specific effector that promotes apoptosis and cell cycle arrest. Direct binding assay (GTP-dependent interaction), overexpression with apoptosis/cell cycle readouts The Journal of biological chemistry High 12732644
2005 RASSF2 expression induces morphological changes and apoptosis in colorectal cancer cells; a deletion mutant lacking the RA domain shows reduced pro-apoptotic activity, indicating the Ras interaction is important for its apoptotic function. Colony formation assay, flow cytometry, immunofluorescence microscopy, deletion mutant analysis Gastroenterology Medium 16012945
2007 RASSF2 contains a functional bipartite nuclear localization signal (NLS); mutation of this NLS abolishes nuclear localization and diminishes its tumor suppressor/growth-suppressive activity, demonstrating that nuclear localization is required for function. NLS mutagenesis, immunofluorescence localization, in vitro and in vivo growth suppression assays Oncogene High 17891178
2008 A RASSF2 deletion mutant lacking the RA domain is unable to interact with Ras and exhibits less pro-apoptotic activity than full-length RASSF2, indicating the Ras-association domain is required for full pro-apoptotic activity in oral squamous cell carcinoma cells. Deletion mutant expression, apoptosis assays Cancer science Medium 18294275
2009 RASSF2 associates with proapoptotic kinases MST1 and MST2 (confirmed at endogenous levels by co-immunoprecipitation), co-immunoprecipitates active MST1/2, is phosphorylated by co-immunoprecipitating MST1/2, and stabilizes MST2 by protecting it from proteolytic degradation. RASSF2 and MST2 colocalize; RASSF2 alone is nuclear but relocalizes to the cytoplasm in the presence of MST1 or MST2. Reciprocal co-immunoprecipitation at endogenous levels, stable and transient expression, siRNA knockdown, colocalization by immunofluorescence, kinase activity assay Oncogene High 19525978
2009 MST1 kinase regulates RASSF2 protein stability (MST1 knockdown destabilizes RASSF2; Mst1-deficient mice show reduced Rassf2 protein). Conversely, RASSF2 activates MST1 kinase activity through formation of a RASSF2-MST1 complex, which inhibits the MST1-FOXO3 signaling pathway. RASSF2 also engages the JNK pathway to induce apoptosis in an MST1-independent manner. siRNA knockdown, complex formation assay, kinase activity assay, mouse knockout model, pathway analysis Biochemical and biophysical research communications High 19962960
2009 RASSF2 contains a functional nuclear export signal (NES) in amino acids 240-260 (C-terminus); substitution of Ile254, Val257, Leu259 impairs nuclear export. Wild-type RASSF2 interacts with export receptor CRM-1 and is exported from the nucleus. ERK2 phosphorylates RASSF2, and MAPK pathway inhibition blocks RASSF2 phosphorylation and nuclear export. Nuclear import-defective RASSF2 fails to induce G1/S cell cycle arrest and apoptosis, demonstrating that nuclear localization is required for growth control. NES mutagenesis, leptomycin B treatment, CRM-1 co-immunoprecipitation, in vitro phosphorylation assay, MAPK inhibitors, cell cycle/apoptosis analysis Experimental cell research High 19555684
2010 RASSF2 forms a direct and endogenous complex with PAR-4 tumor suppressor; this interaction is regulated by K-Ras and is essential for the full apoptotic effects of PAR-4. RASSF2 modulates the nuclear translocation of PAR-4 from the cytoplasm to the nucleus in prostate tumor cells, providing a mechanism for its biological effects. Co-immunoprecipitation (endogenous), nuclear translocation assay, apoptosis assays with K-Ras regulation Molecular and cellular biology High 20368356
2010 Deletion of the MST interaction domain of RASSF2 significantly reduces apoptosis induction in thyroid cancer cells, demonstrating that the MST1/2 interaction is required for RASSF2-mediated apoptosis. Domain deletion mutagenesis, apoptosis assay Molecular cancer Medium 20920251
2012 RASSF2 and K-Ras form an endogenous complex (validated by co-immunoprecipitation). Loss of RASSF2 expression in lung cancer cells with oncogenic K-Ras results in increased activated AKT levels, indicating that RASSF2 modulates Ras-AKT signaling. Loss of RASSF2 also confers resistance to taxol and cisplatin. Endogenous co-immunoprecipitation, RNAi knockdown, AKT phosphorylation assay, drug resistance assays Molecular biology international Medium 22693671
2012 Rassf2 knockout mice develop bone remodeling defects and hematopoietic anomalies. Rassf2 deficiency suppresses osteoblastogenesis but promotes osteoclastogenesis. RASSF2 associates with IKKα and IKKβ and suppresses IKK activity; Rassf2 deficiency results in NF-κB hyperactivation during osteoclast and osteoblast differentiation. Introduction of RASSF2 or dominant-negative IKK into Rassf2-/- precursors normalizes differentiation. Knockout mouse model, bone marrow transplantation, in vitro differentiation assays, co-immunoprecipitation, IKK activity assay, dominant-negative rescue The EMBO journal High 22227519
2016 Proteomics identified novel RASSF2 interaction partners including C1QBP, Vimentin, Protein phosphatase 1G, and Ribonuclease inhibitor. C1QBP interaction with RASSF2 is enhanced by K-Ras, whereas Vimentin interaction is reduced by K-Ras. RASSF2/K-Ras regulates the acetylation state of Vimentin. Proteomics (mass spectrometry), co-immunoprecipitation validation, acetylation analysis Cancers Medium 26999212
2017 miR-7 targets RASSF2 in cancer-associated fibroblasts; overexpression of miR-7 leads to downregulation of RASSF2, which decreases PAR-4 secretion from fibroblasts and enhances cancer cell proliferation and migration in co-culture. miRNA overexpression/inhibition, co-culture assays, bioinformatics target validation, PAR-4 secretion measurement Oncotarget Medium 27901488
2020 RASSF2 re-expression in t(8;21) AML inhibits leukemia development in multiple models. RASSF2 functions depend on interaction with MST1 and MST2 (Hippo kinases) but are independent of canonical Hippo pathway signaling. Proximity-based biotin labeling (BioID) reveals RASSF2 associates with Rac GTPase-related proteins including the GEF DOCK2. RASSF2 knockdown impairs Rac GTPase activation. Re-expression in AML models, BioID proximity labeling, co-immunoprecipitation, Rac GTPase activation assay, MST1/2 interaction studies Blood cancer journal High 32029705
2026 Cell-surface nucleolin (NCL) interacts with RASSF2 via its RNA-binding domain and facilitates nuclear transport of RASSF2, thereby promoting endothelial cell pyroptosis and inflammatory responses in atherosclerosis; NCL suppression decreases nuclear RASSF2 expression. Immunoprecipitation-mass spectrometry, siRNA knockdown, nuclear fractionation, pyroptosis assays in ApoE-/- mouse model Atherosclerosis Medium 41895182

Source papers

Stage 0 corpus · 25 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 150 12732644
2005 The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Gastroenterology 113 16012945
2009 RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene 69 19525978
2005 RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer. British journal of cancer 61 16265349
2010 Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences. Molecular cancer 47 20920251
2009 Role of the tumor suppressor RASSF2 in regulation of MST1 kinase activity. Biochemical and biophysical research communications 47 19962960
2017 Cancer-associated fibroblasts promote cancer cell growth through a miR-7-RASSF2-PAR-4 axis in the tumor microenvironment. Oncotarget 46 27901488
2008 Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma. Cancer science 42 18294275
2007 Epigenetic regulation of the ras effector/tumour suppressor RASSF2 in breast and lung cancer. Oncogene 42 17891178
2019 The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2. Oncology letters 41 31565080
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 28 23542458
2010 The Ras effector RASSF2 controls the PAR-4 tumor suppressor. Molecular and cellular biology 26 20368356
2007 Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers. International journal of oncology 26 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 16 22693671
2020 The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling. Blood cancer journal 12 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 9 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 1 38036076
2019 Association Between RASSF2 Methylation and Gastric Cancer: A PRISMA-Compliant Systematic Review and Meta-Analysis. DNA and cell biology 1 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