Affinage

RANBP3

Ran-binding protein 3 · UniProt Q9H6Z4

Length
567 aa
Mass
60.2 kDa
Annotated
2026-06-10
13 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RANBP3 is a nuclear Ran-binding protein that operates at the heart of CRM1-dependent nuclear export, acting both as a CRM1 cofactor and as a stand-alone export receptor for specific signaling effectors (PMID:9637251, PMID:11571268). It binds RanGTP with unusually low affinity and assembles a trimeric complex with CRM1 and RanGTP, where it stabilizes CRM1–NES cargo interactions and reshapes CRM1's affinity for different export substrates rather than serving as a cargo itself (PMID:11571268, PMID:21364925); structural analysis of its Ran-binding domain explains why RANBP3 promotes export-complex assembly instead of the cytosolic disassembly carried out by RanBP1/RanBP2 (PMID:21364925). This cofactor role is particularly important for weak-NES cargoes: RANBP3 is required to export ERK while being dispensable for strong-NES substrates (PMID:26763446), and it recruits RanGTP into a quaternary CRM1–HBV RNA–RANBP3–RanGTP complex needed for viral RNA export and replication (PMID:42059628). Independently of CRM1, RANBP3 directly recognizes dephosphorylated Smad2/3 and exports them to terminate TGF-beta signaling (PMID:19289081), and binds dephosphorylated (active) beta-catenin in a RanGTP-stimulated manner to drive its nuclear exit and dampen Wnt target-gene transcription (PMID:16314428). Its export activity is regulated by PPM1A, which dephosphorylates RANBP3 at Ser58 to enhance Smad2/3 export (PMID:21960005), and its own nuclear import is directed by an N-terminal NLS preferentially recognized by importin-alpha3 (PMID:10567565). The small molecule NU2058 targets RANBP3 to enhance its beta-catenin interaction and suppress Wnt-driven proliferation (PMID:36270974).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 Medium

    Established RANBP3 as a nuclear member of the Ran pathway, defining the protein's basic identity and RanGTP-preferential binding before any functional role was known.

    Evidence Yeast two-hybrid, cDNA cloning, and immunofluorescence localization

    PMID:9637251

    Open questions at the time
    • No functional output of the Ran interaction defined
    • Whether it acts in import or export unresolved
  2. 1999 High

    Resolved how the nuclear protein itself reaches the nucleus, identifying an unusual N-terminal NLS with isoform-selective importin-alpha recognition.

    Evidence Microinjection, deletion mapping, and recombinant importin-alpha binding across five isoforms

    PMID:10567565

    Open questions at the time
    • Functional consequence of importin-alpha3 selectivity unknown
    • No link to regulation of export activity
  3. 2001 High

    Defined RANBP3's central mechanism as a CRM1 cofactor that stabilizes export complexes and tunes cargo selectivity, distinguishing it from a simple export substrate.

    Evidence In vitro trimeric-complex reconstitution, permeabilized-cell export assay, and substrate-affinity assay

    PMID:11571268

    Open questions at the time
    • Structural basis of assembly-versus-disassembly behavior not yet shown
    • Physiological cargoes not identified
  4. 2003 Medium

    Mapped the CRM1 surface that binds RANBP3 and showed it overlaps a viral-protein interaction site, revealing CRM1 as a multifunctional platform.

    Evidence CRM1 chimeric mutagenesis with Rex multimerization and export functional readouts

    PMID:14612415

    Open questions at the time
    • Reciprocal RANBP3 interface residues not mapped
    • Single-lab functional assays without structural confirmation
  5. 2005 High

    Identified a CRM1-independent function: RANBP3 acts as a direct export receptor for active beta-catenin, linking it to Wnt signaling control.

    Evidence RanGTP-marker yeast two-hybrid, direct binding, RNAi and overexpression with localization in Xenopus and Drosophila

    PMID:16314428

    Open questions at the time
    • Mechanism of CRM1-independent translocation unclear
    • How discrimination of dephosphorylated beta-catenin is achieved not defined
  6. 2009 High

    Extended RANBP3's receptor role to TGF-beta signaling, showing it exports dephosphorylated Smad2/3 to terminate the pathway.

    Evidence Reciprocal binding, co-IP, RNAi, overexpression, dominant-negative constructs, and Xenopus assay

    PMID:19289081

    Open questions at the time
    • Structural basis of dephospho-Smad recognition unknown
    • Coordination with CRM1-cofactor role not addressed
  7. 2011 High

    Provided the structural rationale for RANBP3's unique behavior, explaining its low Ran affinity and its promotion of export-complex assembly versus RanBP1/2 disassembly.

    Evidence X-ray crystallography of the RANBP3 Ran-binding domain with comparative structural analysis

    PMID:21364925

    Open questions at the time
    • No structure of full export complex with cargo
    • Receptor activity toward Smad/beta-catenin not structurally explained
  8. 2011 High

    Established post-translational regulation of RANBP3, showing PPM1A dephosphorylates Ser58 to enhance Smad2/3 export.

    Evidence In vitro phosphatase assay, co-IP, PPM1A-null MEFs, and functional export readout

    PMID:21960005

    Open questions at the time
    • Kinase responsible for Ser58 phosphorylation not identified
    • Effect of Ser58 status on CRM1-cofactor activity untested
  9. 2016 Medium

    Demonstrated cargo selectivity in vivo: RANBP3 is required for export of weak-NES ERK but not strong-NES cargoes, with downstream consequences for apoptotic signaling.

    Evidence shRNA loss-of-function with immunofluorescence localization in melanoma lines

    PMID:26763446

    Open questions at the time
    • Direct ERK–RANBP3 binding not shown
    • Generality across weak-NES cargoes not tested
  10. 2022 Medium

    Showed RANBP3 is a druggable node, with NU2058 enhancing its beta-catenin export activity to suppress Wnt-driven proliferation.

    Evidence LiP-SMap/MS target ID, co-IP, beta-catenin localization, and tumor models

    PMID:36270974

    Open questions at the time
    • Binding site of NU2058 on RANBP3 not mapped
    • Selectivity over other Ran-pathway proteins not established
  11. 2026 Medium

    Extended the cofactor function to viral RNA export, showing RANBP3 recruits RanGTP into a quaternary complex required for HBV RNA export and replication.

    Evidence RNAi of RANBP3/RAN, CRM1 mutagenesis, and RNA export and replication assays

    PMID:42059628

    Open questions at the time
    • No structural validation of the quaternary complex
    • Direct RANBP3–HBV RNA contacts not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RANBP3 mechanistically switches between its CRM1-cofactor mode and its CRM1-independent receptor mode, and how phosphorylation state coordinates these activities, remains unresolved.
  • No structure of a cargo-bound receptor complex
  • Kinase setting Ser58 phosphorylation unidentified
  • Integration of cofactor and receptor roles in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0140104 molecular carrier activity 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953854 Metabolism of RNA 1
Partners
CTNNB1KPNA4MAPK1PPM1ARANSMAD2SMAD3XPO1
Complex memberships
CRM1–RanGTP–RanBP3 export complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RanBP3 was identified as a nuclear Ran-binding protein that preferentially binds RanGTP and contains FXFG nucleoporin motifs and a C-terminal RanBP1-like domain; it was localized to the nucleus and proposed to act as a nuclear effector of the Ran pathway. Yeast two-hybrid, cDNA cloning, subcellular localization by immunofluorescence FEBS letters Medium 9637251
1999 RanBP3 contains an unusual N-terminal nuclear localization signal (residues 40–57) that is imported preferentially by importin-alpha3 (and alpha4), rather than equivalently by all importin-alpha isoforms as seen with the SV40 T-antigen NLS; nuclear import requires importin-alpha and importin-beta. Microinjection of GST-GFP-RanBP3 fusions, deletion analysis, recombinant importin-alpha binding assays, competitive inhibition Molecular and cellular biology High 10567565
2001 RanBP3 interacts directly with CRM1 and forms a trimeric complex with CRM1 and RanGTP; it acts as a cofactor that stabilizes CRM1–export substrate interactions (rather than acting as an export substrate itself) and stimulates CRM1-dependent protein export in permeabilized cells; it also alters the relative affinity of CRM1 for different NES-containing substrates. In vitro binding assays, permeabilized-cell export assay, co-immunoprecipitation EMBO reports High 11571268
2003 The CRM1 region comprising residues 411, 414, 474, and 481 constitutes the binding interface for RanBP3; residues 411 and 414 additionally overlap with the domain required for HTLV-1 Rex multimerization, revealing a multifunctional surface on CRM1. Human/rat CRM1 chimeric mutant analysis, functional Rex multimerization and export assays Molecular and cellular biology Medium 14612415
2005 RanBP3 directly binds active (dephosphorylated) beta-catenin in a RanGTP-stimulated manner and promotes nuclear export of beta-catenin independently of APC and CRM1; RanBP3 depletion increases nuclear dephosphorylated beta-catenin and Wnt target gene transcription, while overexpression shifts active beta-catenin to the cytoplasm. Yeast two-hybrid screen with RanGTP marker, direct binding assays, RNAi depletion, overexpression, beta-catenin localization by immunofluorescence, Xenopus and Drosophila epistasis The Journal of cell biology High 16314428
2009 RanBP3 directly recognizes dephosphorylated Smad2/3 (produced by nuclear Smad phosphatases) and mediates their nuclear export in a Ran-dependent manner, thereby terminating TGF-beta signaling; depletion of RanBP3 enhances TGF-beta antiproliferative and transcriptional responses, while overexpression inhibits them. Direct binding assays, co-immunoprecipitation, RNAi knockdown, overexpression, dominant-negative constructs, Xenopus embryo functional assay Developmental cell High 19289081
2011 Crystal structure of the RanBP3 Ran-binding domain (RBD) reveals structural differences from RanBP1 and RanBP2 RBDs that explain why RanBP3 binds Ran with unusually low affinity, how it modulates CRM1 cargo selectivity, and why it promotes export complex assembly (rather than disassembly as RanBP1/2 do in the cytosol). X-ray crystallography of RanBP3 RBD, structural comparison with RanBP1/RanBP2 RBD–Ran–CRM1 complexes PloS one High 21364925
2011 Protein phosphatase PPM1A directly interacts with and dephosphorylates RanBP3 at Ser58 in vitro and in vivo; dephosphorylation at Ser58 enhances the ability of RanBP3 to export Smad2/3 and terminate TGF-beta signaling; RanBP3 phosphorylation is elevated in PPM1A-null MEFs. In vitro phosphatase assay, co-immunoprecipitation, PPM1A-null MEFs, functional nuclear export assay EMBO reports High 21960005
2016 RanBP3 is required for nuclear export of ERK (a weak-NES cargo) but is dispensable for CRM1-mediated export of strong-NES cargoes; RanBP3 silencing causes ERK nuclear entrapment and increases cytoplasmic non-phosphorylated (active) pro-apoptotic BAD, suggesting ERK nuclear exit depends on RanBP3. shRNA loss-of-function, NES analysis, immunofluorescence-based protein localization in melanoma cell lines The Journal of investigative dermatology Medium 26763446
2022 Small molecule NU2058 directly targets RanBP3 (identified by LiP-SMap/MS) and increases the RanBP3–beta-catenin interaction, promoting nuclear export of beta-catenin and suppressing transcription of c-Myc and cyclin D1, inducing cell senescence in colorectal cancer cells. LiP-SMap/mass spectrometry target identification, co-immunoprecipitation, beta-catenin localization, in vitro and in vivo tumor models Advanced science Medium 36270974
2026 RANBP3 recruits RAN-GTP to assemble an export-competent quaternary complex (CRM1–HBV RNAs–RANBP3–RAN-GTP) required for nuclear export of HBV RNAs; knockdown of RANBP3 or RAN, or CRM1 mutations blocking cofactor binding, severely impairs HBV RNA export and viral replication. RNAi knockdown of RANBP3/RAN, CRM1 mutagenesis, RNA export and viral replication assays Journal of virology Medium 42059628

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 RanBP3 influences interactions between CRM1 and its nuclear protein export substrates. EMBO reports 95 11571268
2009 Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Developmental cell 87 19289081
2005 RanBP3 enhances nuclear export of active (beta)-catenin independently of CRM1. The Journal of cell biology 79 16314428
1999 RanBP3 contains an unusual nuclear localization signal that is imported preferentially by importin-alpha3. Molecular and cellular biology 69 10567565
1998 Human RanBP3, a group of nuclear RanGTP binding proteins. FEBS letters 59 9637251
2003 A multifunctional domain in human CRM1 (exportin 1) mediates RanBP3 binding and multimerization of human T-cell leukemia virus type 1 Rex protein. Molecular and cellular biology 30 14612415
2011 PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3. EMBO reports 28 21960005
2022 Blockade of Nuclear β-Catenin Signaling via Direct Targeting of RanBP3 with NU2058 Induces Cell Senescence to Suppress Colorectal Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 23 36270974
2011 Insights into the function of the CRM1 cofactor RanBP3 from the structure of its Ran-binding domain. PloS one 16 21364925
2016 RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export. The Journal of investigative dermatology 7 26763446
2021 RanBP3 Regulates Proliferation, Apoptosis and Chemosensitivity of Chronic Myeloid Leukemia Cells via Mediating SMAD2/3 and ERK1/2 Nuclear Transport. Frontiers in oncology 4 34504783
2024 Value of altered methylation patterns of genes RANBP3, LCP2 and GRAP2 in cfDNA in breast cancer diagnosis. Journal of medical biochemistry 3 39139156
2026 RANBP3 and RAN orchestrate CRM1-mediated nuclear export of hepatitis B virus RNAs. Journal of virology 0 42059628

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