{"gene":"RANBP9","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1998,"finding":"RanBPM (RanBP9) was identified as a centrosomal protein that binds GTP-Ran and is required for microtubule nucleation; overexpression produced ectopic microtubule nucleation sites co-localizing with gamma-tubulin, and anti-RanBPM antibodies inhibited microtubule aster formation.","method":"Yeast two-hybrid (Ran bait), sucrose-density gradient centrifugation, immunofluorescence, antibody inhibition assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, fractionation, antibody inhibition) in single lab; centrosomal localization later revised by full-length cDNA study","pmids":["9817760"],"is_preprint":false},{"year":2001,"finding":"The originally described 55 kDa RanBPM was a truncated isoform; the full-length protein is 90 kDa with an N-terminal proline/glutamine-rich region, forms a >670 kDa complex, and localizes predominantly to nucleus and cytoplasm surrounding the centrosome—not within the centrosome itself.","method":"Full-length cDNA cloning, immunoblotting with antibodies against three distinct regions, gel filtration, immunofluorescence","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct molecular characterization with multiple antibodies and size-exclusion; revised prior model with rigorous controls","pmids":["11470507"],"is_preprint":false},{"year":2002,"finding":"RanBPM interacts with the tyrosine kinase domain of MET receptor via its SPRY domain; RanBPM activates the Ras-Erk-SRE pathway by recruiting Sos to the MET complex, functioning as an adaptor protein.","method":"Yeast two-hybrid, in vitro GST pull-down, co-immunoprecipitation, Ras-GTP loading assay, ERK phosphorylation assay, SRE-luciferase reporter, cell migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, GST pull-down, Co-IP, functional reporter, migration assay) in single rigorous study","pmids":["12147692"],"is_preprint":false},{"year":2002,"finding":"RanBPM interacts with androgen receptor (AR) and glucocorticoid receptor (GR), but not estrogen receptor, and enhances their transcriptional activity in a ligand-dependent manner when overexpressed in prostate cancer cells.","method":"Yeast two-hybrid, GST pull-down, His-tag pull-down, transient overexpression with luciferase reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down plus functional reporter, single lab","pmids":["12361945"],"is_preprint":false},{"year":2002,"finding":"USP11, a ubiquitin-specific protease, interacts with RanBPM and deubiquitinates it; RanBPM undergoes proteasome-dependent degradation and is ubiquitinated in vivo and in vitro, and USP11 inhibits this ubiquitination in a dose-dependent manner.","method":"Yeast two-hybrid, co-immunoprecipitation, pulse-chase analysis with proteasome inhibitors, in vivo and in vitro ubiquitination assays, recombinant USP11 inhibition assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay plus in vivo co-IP, pulse-chase, and enzymatic inhibition providing multiple orthogonal methods","pmids":["12084015"],"is_preprint":false},{"year":2002,"finding":"HIPK2 (homeodomain-interacting protein kinase 2) interacts with RanBPM in the nucleus of mammalian cells; both wild-type HIPK2 and a kinase-dead HIPK2 mutant co-localize with RanBPM in defined nuclear structures.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, immunofluorescence co-localization","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-IP plus co-localization only, no functional consequence established","pmids":["12220523"],"is_preprint":false},{"year":2003,"finding":"RanBPM forms a protein complex with Twa1 and Muskelin (hMuskelin), as demonstrated by co-immunoprecipitation and gel-filtration analysis; all three proteins share the LisH-CTLH motif.","method":"Yeast two-hybrid, co-immunoprecipitation, gel-filtration chromatography","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus gel filtration, single lab","pmids":["12559565"],"is_preprint":false},{"year":2003,"finding":"RanBPM interacts with the death domain of p75NTR neurotrophin receptor intracellular domain.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP with domain mapping, no downstream functional readout","pmids":["12963025"],"is_preprint":false},{"year":2003,"finding":"CDK11(p46), a caspase-processed apoptotic kinase, directly interacts with RanBPM via its SPRY domain and phosphorylates RanBPM in vitro.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation in human cells, in vitro kinase assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus Co-IP, single lab","pmids":["14511641"],"is_preprint":false},{"year":2004,"finding":"RanBPM is a peripheral plasma membrane protein that interacts with the cytoplasmic domain of integrin LFA-1 (beta2) and beta1 integrin via in vitro and in vivo assays; RanBPM is phosphorylated on serine residues and this phosphorylation is regulated by p38 kinase activity; RanBPM synergizes with LFA-1 in AP-1-dependent transcriptional activation.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, membrane fractionation, phosphorylation assays with p38 inhibitor SB203580, luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including membrane fractionation, Co-IP, phosphorylation analysis, and functional reporter in single rigorous study","pmids":["14722085"],"is_preprint":false},{"year":2004,"finding":"RanBPM interacts with the tyrosine kinase domain of Axl and Sky/Tyro3 receptor tyrosine kinases via its SPRY-LisH domain region; a truncated RanBPM lacking this region fails to interact with Axl; endogenous Axl and RanBPM interact constitutively in multiple mammalian cell lines.","method":"Yeast two-hybrid, co-immunoprecipitation in cell-free and mammalian cell systems, domain deletion analysis, Gas6 stimulation experiment","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and endogenous interaction confirmed, single lab","pmids":["15964779"],"is_preprint":false},{"year":2004,"finding":"Mouse RanBPM interacts with the germline-specific RNA helicase MVH (mouse vasa homolog) in testicular germ cells; both proteins associate with perinuclear RNA-protein complexes and chromatoid bodies.","method":"Yeast two-hybrid, co-localization by immunofluorescence in testis","journal":"Molecular reproduction and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Y2H plus co-localization only, no biochemical confirmation of direct interaction in vivo","pmids":["14648869"],"is_preprint":false},{"year":2005,"finding":"RanBPM interacts with p73alpha (but not p53) through the extreme C-terminal region of p73alpha; RanBPM stabilizes p73alpha by inhibiting its ubiquitination, thereby prolonging its half-life and enhancing its proapoptotic activity; co-expression causes nuclear co-localization of RanBPM and p73alpha.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunofluorescence, ubiquitination assay, half-life analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and half-life analysis in single lab","pmids":["15558019"],"is_preprint":false},{"year":2005,"finding":"RanBPM interacts with the cytoplasmic domain of neural cell adhesion molecule L1 via its N-terminal SPRY domain; overexpression of N-RanBPM reduces L1-triggered ERK1/2 activation by 50% and inhibits L1-mediated neurite outgrowth and branching.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, L1 antibody patching/subcellular redistribution, ERK activation assay, primary neuron morphology","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down, Co-IP, and functional ERK/neurite assays, single lab","pmids":["16000162"],"is_preprint":false},{"year":2005,"finding":"RanBPM interacts with TAF4 (a TFIID subunit); co-transfection of TAF4 and RanBPM increases primary neurite processes in neural progenitors; the effect is abolished by a TAF4 isoform lacking the RanBPM-interacting domain.","method":"Protein-protein interaction screen, co-immunoprecipitation from neural stem cell extracts, co-transfection/morphology assay","journal":"Molecular and cellular neurosciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP plus functional morphology assay, single lab, limited mechanistic follow-up","pmids":["15911349"],"is_preprint":false},{"year":2006,"finding":"RanBPM associates with the N-terminus of CD39/ecto-NTPDase1; co-expression of RanBPM substantially reduces NTPDase activity of recombinant CD39 but not of an N-terminus-deleted CD39 mutant, demonstrating functional regulation of ecto-nucleotidase activity.","method":"Yeast two-hybrid, co-immunoprecipitation in transfected mammalian cells, NTPDase activity assay, domain deletion mutant analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay with mutant validation plus Co-IP, single lab","pmids":["16478441"],"is_preprint":false},{"year":2006,"finding":"RanBPM physically interacts with Plexin-A1 and mediates Semaphorin3A signaling; overexpression of RanBPM with Plexin-A1 reduces cell spreading and inhibits axonal outgrowth in vitro and in vivo; a truncated RanBPM blocks Sema3A responsiveness; RanBPM knockdown reduces Sema3A responsiveness; the RanBPM/Plexin-A1 complex is regulated by MICAL expression.","method":"Domain-based interaction screen, co-immunoprecipitation, overexpression and truncation/knockdown functional assays in neurons and non-neuronal cells, in vivo axon guidance assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, multiple gain/loss-of-function experiments, both in vitro and in vivo validation","pmids":["16672672"],"is_preprint":false},{"year":2006,"finding":"RanBPM interacts with TrkA via its SPRY motif (binding at TrkA tyrosine kinase domain); overexpression of RanBPM inhibits NGF-induced NFAT-dependent luciferase expression.","method":"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, NFAT-luciferase reporter assay","journal":"Neuroscience letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and GST pull-down plus single functional reporter assay, single lab","pmids":["16959415"],"is_preprint":false},{"year":2006,"finding":"RanBPM is a coactivator of thyroid hormone receptors (TRs); it binds TRs in a ligand-independent manner via its C-terminal region interacting with the TR DNA-binding domain; overexpression enhances TR-dependent transcriptional activation, whereas the truncated RanBPM55 lacking the N-terminal polyglutaminated region inhibits it in a dominant-negative manner.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, transient transfection luciferase reporter, domain deletion competition assays","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down, Co-IP, and functional luciferase assays with deletion analysis, single lab","pmids":["16595702"],"is_preprint":false},{"year":2007,"finding":"RanBPM is a component of a large protein complex (renamed CTLH complex) composed of Muskelin, p48EMLP, p44CTLH, ARMC8alpha, and ARMC8beta; each component was confirmed by co-immunoprecipitation and in vitro Twa1 pull-down.","method":"Tandem MS with anti-RanBPM antibody immunoprecipitation from HEK293 cells, co-immunoprecipitation in Cos-7 cells, in vitro pull-down with bacterially expressed Twa1","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mass spectrometry identification confirmed by independent Co-IP and in vitro pull-down across multiple components","pmids":["17467196"],"is_preprint":false},{"year":2008,"finding":"Muskelin subcellular localization is co-regulated with RanBP9; knockdown of muskelin or RanBP9 both produce protrusive cell morphologies with enlarged cell perimeters; RanBP9 binding via the muskelin C-terminus is required to restore normal morphology, identifying a muskelin-RanBP9 complex as a nucleocytoplasmic mediator of cell morphology.","method":"Subcellular fractionation, siRNA knockdown, rescue with cDNA variants, cell morphology quantification","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with rescue, subcellular fractionation, multiple cDNA variants tested; single lab","pmids":["18710924"],"is_preprint":false},{"year":2008,"finding":"RanBPM interacts with metabotropic glutamate receptors mGlu2 and other group II and group III receptors (except mGlu6) in the retina, co-localizing with mGlu8b in the inner plexiform layer.","method":"Yeast two-hybrid (mGlu8 bait), co-immunoprecipitation, immunofluorescence co-localization in retina sections","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Y2H plus Co-IP and co-localization, no functional downstream assay, single lab","pmids":["18555800"],"is_preprint":false},{"year":2008,"finding":"RanBPM interacts with p42(IP4)/Centaurin-alpha-1 via its SPRY domain; D-Ins(1,3,4,5)P4 (a specific ligand for p42(IP4)) inhibits this interaction in a concentration-dependent and stereoselective manner.","method":"Co-immunoprecipitation with endogenous RanBPM from rat brain, in vitro binding assay, inositol phosphate competition assay, domain mapping with SPRY domain","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous Co-IP from brain plus in vitro ligand competition, single lab","pmids":["18298663"],"is_preprint":false},{"year":2008,"finding":"RanBPM interacts with Rta (EBV immediate-early protein) via the SPRY domain of RanBPM; this interaction promotes Rta transactivation activity, and mechanistically RanBPM interacts with SUMO-E2 (Ubc9) to enhance sumoylation of Rta by SUMO-1.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal co-localization, transient transfection reporter assay, sumoylation assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, sumoylation assay, reporter assay; single lab; functional mechanism proposed through sumoylation","pmids":["18455188"],"is_preprint":false},{"year":2008,"finding":"RanBPM modulates T-type Ca2+ channel Cav3.1 by binding its intracellular loop between transmembrane domains I and II; RanBPM expression increases Cav3.1 currents and abolishes PKC activator-mediated inhibition of these currents.","method":"Yeast two-hybrid, whole-cell patch-clamp electrophysiology, domain binding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — electrophysiology with domain-level interaction mapping, single lab","pmids":["18801335"],"is_preprint":false},{"year":2008,"finding":"Drosophila RanBPM is required for normal germline stem cell (GSC) niche organization; loss of the long RanBPM isoform causes defects in niche cell size, niche organization, and abnormal accumulation of adherens junction component Armadillo (beta-catenin), increasing GSC attachment to niche cap cells.","method":"Drosophila genetics (null and isoform-specific alleles), mosaic analysis, immunofluorescence for Armadillo and Hts","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with molecular marker analysis, Drosophila model","pmids":["18762575"],"is_preprint":false},{"year":2009,"finding":"RanBPM promotes BACE1 cleavage of APP and Abeta generation; RanBP9 N-terminal SPRY-LisH domain interacts with LRP, APP, and BACE1 simultaneously, scaffolding these proteins together; RanBP9 reduces cell surface APP, accelerates APP internalization, and increases lipid raft association of APP; knockdown of endogenous RanBP9 significantly reduces Abeta generation in CHO cells and primary neurons.","method":"Co-immunoprecipitation, cell surface biotinylation, endocytosis assay, lipid raft fractionation, siRNA knockdown, Abeta ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including endocytosis assay, raft fractionation, knockdown in primary neurons, replicated across cell types","pmids":["19251705"],"is_preprint":false},{"year":2009,"finding":"A processed form of RanBP9 (RanBP9-N60, residues 1-392) lacks a nuclear localization signal, displays enhanced cytoplasmic localization and >3-fold enhanced stability compared to full-length RanBP9, retains capacity to form self-interacting multimeric complexes via LisH domain, and potentiates Abeta generation ~5-fold.","method":"Deletion mutant analysis, subcellular fractionation, protein stability assays, Abeta ELISA","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutant characterization with functional readout, single lab","pmids":["19729516"],"is_preprint":false},{"year":2009,"finding":"RanBPM has proapoptotic activity: transient expression induces caspase activation; the C-terminal domain stimulates this activity while the central SPRY domain negatively regulates it; RanBPM knockdown prevents DNA damage-induced caspase-3 and caspase-2 activation; following ionizing radiation, RanBPM relocalizes from nucleus to cytoplasm; RanBP9 downregulation decreases mitochondria-associated Bax and increases Bcl-2.","method":"Transient expression, siRNA knockdown, caspase activation assay, immunofluorescence for relocalization, Bax/Bcl-2 western blot","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain analysis, siRNA knockdown with multiple readouts, single lab","pmids":["19996306"],"is_preprint":false},{"year":2009,"finding":"RanBPM interacts with acetylcholinesterase (AChE) C-terminal domain and translocates from the cytoplasm to the nucleus during cisplatin-induced apoptosis, similar to AChE.","method":"Yeast two-hybrid, co-immunoprecipitation, immunoblotting of cytoplasmic and nuclear fractions","journal":"Acta biochimica et biophysica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and fractionation, single lab, limited functional follow-up","pmids":["19902122"],"is_preprint":false},{"year":2010,"finding":"RanBPM interacts with citron kinase (CITK) at adherens junctions of the neocortical ventricular surface; RanBPM knockdown decreases CITK polarization to the ventricular surface, increases mitotic cells, and decreases cytokinetic cells; the CITK mutation rescues the RanBPM knockdown mitosis phenotype, placing RanBPM upstream of CITK in M-phase progression.","method":"Yeast two-hybrid, co-immunoprecipitation, protein overlay, in utero RNAi, genetic epistasis with CITK mutant","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus Co-IP and in vivo RNAi, single lab","pmids":["19790105"],"is_preprint":false},{"year":2010,"finding":"RanBPM interacts with TrkB receptor and contributes to BDNF-induced MAPK and Akt activation; RanBPM overexpression enhances BDNF-induced MAPK/Akt signaling; RanBPM siRNA knockdown has opposite effects; RanBPM promotes BDNF-induced hippocampal neuronal morphogenesis and BDNF-mediated survival.","method":"Co-immunoprecipitation, overexpression and siRNA knockdown, phospho-MAPK/Akt western blot, neuronal morphology and survival assays","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with multiple readouts, single lab","pmids":["20403074"],"is_preprint":false},{"year":2010,"finding":"RanBPM interacts with YPEL5 protein; RanBPM was identified as a YPEL5-binding protein and their interaction was confirmed by yeast two-hybrid.","method":"Yeast two-hybrid","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — Y2H only, no biochemical confirmation or functional consequence for RanBPM specifically","pmids":["20580816"],"is_preprint":false},{"year":2010,"finding":"RanBPM interacts with Mgl-1 (mammalian Lgl1); RanBPM inhibits Mgl-1 proteasomal degradation and extends its half-life; RanBPM enhances Mgl-1 activity in cell migration and colony formation assays.","method":"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, protein stability assay, cell migration and colony formation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, GST pull-down, stability assay, functional assays; single lab","pmids":["20829363"],"is_preprint":false},{"year":2011,"finding":"RanBPM is essential for mammalian gametogenesis: RanBPM-null mice of both sexes are sterile; males show spermatogenesis arrest at late pachytene-diplotene prophase I without chromosome synapsis defects; females show premature ovarian failure at prophase I; chimera experiments demonstrate cell-autonomous function in germ cells.","method":"Gene knockout in mice, histological analysis, meiotic staging, chimeric mouse generation with knockout ES cells","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout phenotype with mechanistic stage determination, cell-autonomous demonstration via chimeras","pmids":["21561988"],"is_preprint":false},{"year":2012,"finding":"RanBP9 overexpression disrupts integrin-dependent cell attachment, spreading, and focal adhesion signaling (Pyk2/paxillin), while knockdown promotes these processes; RanBP9 accelerates endocytosis of β1-integrin, LRP, and APP; primary hippocampal neurons from RanBP9-transgenic mice show reduced surface β1-integrin, LRP, APP, and neurite arborization.","method":"Cell attachment/spreading assays, focal adhesion immunostaining, cell surface biotinylation, endocytosis assay, siRNA knockdown, primary neuron from transgenic mice","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays with both gain and loss of function, in vitro and in vivo validation","pmids":["22223749"],"is_preprint":false},{"year":2012,"finding":"RanBP9 activates/dephosphorylates cofilin and promotes Abeta-induced apoptosis; siRNA knockdown of cofilin abolishes both Abeta- and RanBP9-induced apoptosis, placing cofilin downstream of RanBP9 in the apoptotic pathway.","method":"siRNA knockdown (cofilin, RanBP9), cofilin phosphorylation western blot, apoptosis assays (RanBP9-Tg mice), spatial memory testing","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via siRNA, in vivo transgenic model, multiple readouts; single lab","pmids":["22361682"],"is_preprint":false},{"year":2012,"finding":"RanBP9 overexpression in mice leads to >2-fold increase in Abeta40 and Abeta42 levels and increased amyloid plaque deposition; RanBP9-null mice show increased synaptic protein levels (synaptophysin, PSD-95, drebrin A).","method":"Transgenic and null mouse generation, ELISA for Abeta, amyloid plaque immunostaining, synaptic protein western blot","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic and null mouse models with multiple biochemical readouts confirming bidirectional regulation","pmids":["22294787"],"is_preprint":false},{"year":2012,"finding":"RanBPM inhibits ERK signaling by forming a complex with c-Raf, decreasing Hsp90 binding to c-Raf, and destabilizing c-Raf protein; RanBPM knockdown stimulates MEK and ERK phosphorylation leading to Bcl-2 upregulation; RanBPM expression prevents MEK/ERK activation by active RasV12 and active c-Raf.","method":"Co-immunoprecipitation (RanBPM-c-Raf complex), Hsp90 binding assay, siRNA/shRNA knockdown, ERK phosphorylation assay, Bcl-2 western blot, cell proliferation and migration assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with multiple functional downstream readouts, single lab; mechanism via Hsp90 displacement from c-Raf","pmids":["23118896"],"is_preprint":false},{"year":2013,"finding":"RanBP9 physically interacts with tumor suppressor p73, increases endogenous p73alpha levels at both transcriptional and post-translational levels, and cooperates with p73 to induce mitochondria-mediated cell death (loss of mitochondrial membrane potential, Bax oligomerization, cytochrome c release); RanBP9 knockdown suppresses p73-induced apoptosis and vice versa.","method":"Co-immunoprecipitation, p73 western blot (transcriptional and stability analysis), siRNA knockdown of p73 and RanBP9, mitochondrial membrane potential assay, Bax oligomerization, cytochrome c release, Mdivi-1/Bcl-2/Bcl-xl inhibitor experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional siRNA epistasis, Co-IP, and multiple orthogonal mitochondrial assays in single rigorous study","pmids":["23348590"],"is_preprint":false},{"year":2013,"finding":"RanBP9 potentiates Abeta-induced ROS overproduction, apoptosis, and calcium deregulation in hippocampal neurons; RanBP9 selectively delays cytosolic Ca2+ clearance by the mitochondrial calcium uniporter through cofilin translocation to mitochondria; RanBP9 retards anterograde axonal transport of mitochondria and decreases synaptic mitochondrial activity.","method":"Primary hippocampal neuron overexpression, ROS assay, Ca2+ imaging, mitochondrial calcium uniporter blockade, cofilin mitochondrial translocation assay, axonal transport live imaging","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in primary neurons, single lab, mechanistic link through cofilin","pmids":["23982146"],"is_preprint":false},{"year":2013,"finding":"COPS5 (Jab1/CSN5) is a novel RanBP9-interacting protein that stabilizes RanBP9 protein levels, thereby increasing Abeta generation; COPS5 increases RanBP9 half-life; COPS5 knockdown reduces Abeta generation.","method":"Yeast two-hybrid (human brain library), co-immunoprecipitation in neuronal and non-neuronal cells and mouse brain, protein half-life assay, siRNA knockdown, Abeta ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in multiple systems, half-life assay, siRNA knockdown with Abeta readout; single lab","pmids":["23926111"],"is_preprint":false},{"year":2013,"finding":"RanBPM interacts with TRAF6 via its SPRY motif; RanBPM inhibits TRAF6 ubiquitination and suppresses TRAF6-triggered NF-κB signaling; RanBPM also blocks TGF-β-induced TβRI nuclear accumulation by competing with TRAF6 for TβRI binding.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal microscopy, FRET, ubiquitination assay, NF-κB reporter assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET plus Co-IP, ubiquitination assay, and functional reporter; single lab","pmids":["24103590"],"is_preprint":false},{"year":2014,"finding":"RanBPM promotes aggresome formation: ionizing radiation and proteasome inhibition cause RanBPM redistribution into perinuclear aggresomes with ubiquitin, dynein, and HDAC6; aggresome formation by HDAC6 is markedly impaired in RanBPM shRNA cells but restored by RanBPM re-expression; RanBPM interacts with HDAC6 via its LisH/CTLH domain and inhibits HDAC6 deacetylase activity.","method":"Immunofluorescence for aggresome markers, shRNA knockdown with rescue, co-immunoprecipitation (RanBPM-HDAC6), deacetylase activity assay, LisH/CTLH deletion mutant analysis","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with domain deletion, enzymatic activity assay, shRNA rescue, multiple orthogonal methods","pmids":["24795145"],"is_preprint":false},{"year":2014,"finding":"AXL, LRP-1, and RANBP9 form a multiprotein complex mediating DC efferocytosis; AXL binds apoptotic cells but requires LRP-1 for internalization; RANBP9 bridges AXL and LRP-1 (which do not interact directly) to form the complex; this complex is required for DC antigen cross-presentation to CD8+ T cells; mice lacking DC-specific LRP-1, AXL, or RANBP9 show increased AC accumulation and defective viral antigen-specific T cell responses.","method":"Targeted genetic deletion in mice, spleen efferocytosis assay, co-immunoprecipitation (AXL-RANBP9-LRP1), DC-T cell coculture cross-presentation assay, HSV-1 infection model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic deletion, Co-IP defining complex, functional efferocytosis and cross-presentation readouts, infection model validation","pmids":["24509082"],"is_preprint":false},{"year":2014,"finding":"RanBP9 physically interacts with tau and Hsp90/Hsc70 chaperone complexes; RanBP9 overexpression or knockdown directly increases or reduces tau levels in vitro and in vivo; RanBP9 enhances Hsp90 and Hsc70 ATPase activities; genetic reduction of RanBP9 ameliorates tauopathy in Tau-P301S mice.","method":"Co-immunoprecipitation (RanBP9-tau-Hsp90/Hsc70), in vitro ATPase assay, RanBP9 overexpression/knockdown western blot, Tau-P301S mouse model genetic reduction","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ATPase assay, Co-IP, in vivo mouse model, bidirectional regulation confirmed across multiple systems","pmids":["29016855"],"is_preprint":false},{"year":2015,"finding":"RanBP9 interacts with HDAC6 and, together with the CTLH complex (via Twa1 and MAEA), inhibits HDAC6 deacetylase activity toward alpha-tubulin; RanBPM associates with microtubules in an HDAC6-dependent manner; RanBPM knockdown-induced increase in cell migration is due to relief of HDAC6 inhibition.","method":"Co-immunoprecipitation of HDAC6 with CTLH complex members, acetylated alpha-tubulin western blot, confocal microscopy, shRNA knockdown of multiple CTLH members, wound-healing migration assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of multiple complex members, functional deacetylase readout, migration rescue; single lab","pmids":["28668087"],"is_preprint":false},{"year":2015,"finding":"RanBPM contains two distinct nuclear localization motifs (N-terminal proline/glutamine-rich region dominant; C-terminal contributes minimally), one nuclear export signal (NES) whose mutation prevents cytoplasmic accumulation, and its cytoplasmic localization is also conferred by protein-protein interactions; in the cytoplasm, RanBPM partially co-localizes with and associates with alpha-tubulin; in the nucleus, RanBPM is associated with chromatin.","method":"Systematic deletion mutant analysis in RanBPM shRNA background, confocal microscopy, microtubule co-localization, chromatin fractionation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain analysis with multiple subcellular localization readouts and biochemical fractionation; single lab","pmids":["25659156"],"is_preprint":false},{"year":2015,"finding":"Endogenous RanBP9 mediates Abeta-induced cofilin translocation to mitochondria via Slingshot homolog 1 (SSH1); RanBP9 positively regulates SSH1 levels; RanBP9 reduction in APP/PS1 mice protects against cofilin-actin pathology, synaptic damage, gliosis, and Abeta accumulation; RanBP9 reduction significantly enhances LTP and partially rescues contextual memory deficits.","method":"siRNA knockdown, primary neuron cofilin translocation assay, in vivo APP/PS1 mouse RanBP9 reduction, LTP electrophysiology, behavioral memory testing","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic reduction with mechanistic (SSH1-cofilin pathway) and functional (LTP, behavior) readouts, replicated in cell and mouse models","pmids":["25741591"],"is_preprint":false},{"year":2016,"finding":"Ran Binding Protein 9 (RanBP9) is phosphorylated by active ATM on at least S181 and S603 in response to ionizing radiation; DNA damage promotes RanBP9 nuclear accumulation in an ATM-dependent manner; RanBP9 silencing causes delayed activation of ATM, Chk2, γH2AX, and p53, and reduces homologous recombination efficiency, leading to enhanced IR-induced senescence and apoptosis.","method":"ATM phosphorylation site identification (S181/S603), ATM inhibition experiments, nuclear accumulation assay, RanBP9 stable silencing in multiple cell lines, ATM/Chk2/γH2AX western blot, homologous recombination reporter assay","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identified phosphorylation sites, ATM inhibition rescue of localization, multiple DDR readouts replicated across three cell lines","pmids":["26943034"],"is_preprint":false},{"year":2016,"finding":"RanBPM/RanBP9 scaffold protein binds c-Kit receptor tyrosine kinase and is required for normal c-Kit protein expression in mouse testis and hematopoietic lineages; RanBPM deletion reduces c-Kit protein but not mRNA, indicating post-translational regulation; this regulation is specific to c-Kit among membrane proteins examined.","method":"Co-immunoprecipitation (RanBPM-c-Kit), western blot (protein vs mRNA comparison), RanBPM-null mice phenotypic analysis, human cell line endogenous expression analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo null mouse phenotype with mRNA/protein dissociation, single lab","pmids":["27835883"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the IUS-SPRY domain of RanBPM was determined; this domain adopts a beta-sandwich fold with a unique shallow binding surface formed by conserved loops, positive patch, and a tryptophan-lined bottom; a 20-mer peptide of DDX-4 (RNA helicase) binds this surface with KD ~13 µM; mutagenesis studies elucidate the interaction interface.","method":"X-ray crystallography of SPRY domain, crystal structure of peptide-domain complex, isothermal titration calorimetry or equivalent binding assay (KD determination), site-directed mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures (apo and complex) with mutagenesis; single lab but Tier 1 method","pmids":["27622290"],"is_preprint":false},{"year":2016,"finding":"RanBP9 SPRY domain interacts with TSSC3 PH domain; RanBP9/TSSC3 complex forms a ternary complex with Src, scaffolding their interaction; this suppresses Src and Src-dependent Akt pathway activation, facilitating mitochondrial-associated anoikis and suppressing lung metastasis in vivo.","method":"Co-immunoprecipitation (RanBP9-TSSC3-Src), domain mapping, anoikis assay, Src/Akt phosphorylation western blot, in vivo lung metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ternary complex with domain mapping, functional anoikis and in vivo metastasis assays; single lab","pmids":["28032865"],"is_preprint":false},{"year":2017,"finding":"CLOCK interacts with RANBP9 (confirmed by yeast two-hybrid and co-immunoprecipitation in mouse testis); RANBP9 previously known to interact with SF3B3 (spliceosome component); CLOCK also interacts with SF3B3; CLOCK binds mRNAs involved in spermatogenesis (demonstrated by RIP-Seq), suggesting CLOCK-RANBP9 involvement in alternative splicing.","method":"Yeast two-hybrid, co-immunoprecipitation in mouse testis, RIP-Seq","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP in testis confirming interaction, but downstream splicing mechanism not directly demonstrated for RanBP9","pmids":["29126923"],"is_preprint":false},{"year":2023,"finding":"RanBP9 physically interacts with p21 and recruits the deubiquitinase USP11 to maintain p21 protein stability by deubiquitination; RanBP9 silencing decreases p21 protein levels whereas overexpression increases p21 independent of p53 status; DNA damage promotes nuclear translocation of RanBP9 via ATM signaling; RanBP9 regulates DDR in a p21-dependent manner.","method":"Co-immunoprecipitation (RanBP9-p21-USP11), in vivo ubiquitylation assay, RanBP9 overexpression/silencing, nuclear translocation assay with ATM inhibition, DDR functional assays","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ternary complex, ubiquitylation assay, p53-independent p21 stabilization demonstrated; single lab","pmids":["37676377"],"is_preprint":false},{"year":2025,"finding":"In lung macrophages, RanBP9-V5 co-immunoprecipitates known CTLH complex members; however, >90% of the lung RanBP9-associated proteome differs between the two tagged versions (V5 vs HA), revealing macrophage-specific interactions with proteins involved in innate immune response, DNA damage response, metabolism, and mitochondrial function.","method":"In vivo knock-in mouse model (RanBP9-TurnX with LysM-Cre), tandem affinity immunoprecipitation with mass spectrometry from lung tissue","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo proteomics with rigorous tag-switching control; single study but novel in vivo approach","pmids":["40223093"],"is_preprint":false},{"year":2025,"finding":"RANBP9 and RANBP10 can each independently support CTLH complex formation; acute overexpression of either Scorpin reshapes the NSCLC cell proteome and ubiquitylome; higher RANBP9/RANBP10 ratio is associated with greater cell proliferation; they act as partial antagonists modulating the CTLH complex ubiquitylation output.","method":"Inducible overexpression/loss-of-function cell lines, proteomics, ubiquitylome profiling, patient tumor lysate analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics and ubiquitylome with inducible cell lines; single lab but orthogonal mass spectrometry approaches","pmids":["40883813"],"is_preprint":false}],"current_model":"RANBP9/RanBPM is a nucleocytoplasmic scaffolding protein that assembles multiprotein complexes through its SPRY and LisH/CTLH domains: it is a core component of the CTLH E3 ubiquitin ligase complex (with Muskelin, Twa1, MAEA, Rmnd5, ARMC8α/β, p48EMLP, and p44CTLH), undergoes ATM-dependent phosphorylation and nuclear translocation after DNA damage where it stabilizes p21 by recruiting USP11, promotes APP/BACE1/LRP scaffolding to drive amyloidogenic processing and β1-integrin/LRP endocytosis, activates cofilin via SSH1 to induce mitochondrial apoptosis, inhibits HDAC6 deacetylase activity to restrain cell migration, bridges AXL and LRP-1 to mediate DC efferocytosis, interacts with and modulates multiple receptor tyrosine kinases (MET, Axl, TrkA, TrkB, c-Kit) and nuclear receptors (AR, GR, TR), is itself subject to proteasomal degradation regulated by USP11 deubiquitination and COPS5-mediated stabilization, and is essential in vivo for gametogenesis in both sexes."},"narrative":{"mechanistic_narrative":"RANBP9 (RanBPM) is a nucleocytoplasmic scaffolding protein that assembles multiprotein complexes through its SPRY and LisH/CTLH domains to coordinate receptor signaling, the DNA damage response, protein turnover, and apoptosis [PMID:17467196, PMID:27622290, PMID:12147692]. It is a core subunit of the large (>670 kDa) CTLH E3 ubiquitin ligase complex together with Muskelin, Twa1, p48EMLP, p44CTLH, ARMC8α/β, and MAEA, and this complex governs HDAC6-dependent α-tubulin deacetylation and cell migration [PMID:11470507, PMID:17467196, PMID:28668087]; its paralog RANBP10 can substitute as the complex-organizing subunit, with the two acting as partial antagonists that tune ubiquitylation output and proliferation [PMID:40883813]. Its β-sandwich SPRY domain presents a shallow conserved binding surface that engages diverse partners, including the tyrosine kinase domains of MET, Axl, TrkA, and c-Kit and the RNA helicase DDX4 [PMID:27622290, PMID:12147692, PMID:15964779, PMID:27835883]; through these interactions RANBP9 acts as an adaptor that recruits Sos to activate Ras-ERK signaling at MET while modulating multiple other receptor and nuclear-receptor outputs [PMID:12147692, PMID:16595702]. In the DNA damage response, RANBP9 is phosphorylated by ATM and translocates to the nucleus, where it promotes efficient ATM/Chk2/γH2AX activation and homologous recombination and stabilizes p21 by recruiting the deubiquitinase USP11 in a p53-independent manner [PMID:26943034, PMID:37676377]; RANBP9 itself is a degradation substrate whose levels are set by USP11 deubiquitination and COPS5-mediated stabilization [PMID:12084015, PMID:23926111]. RANBP9 drives mitochondrial apoptosis by activating cofilin via SSH1 and cooperating with p73, and it promotes amyloidogenic APP processing by scaffolding APP, BACE1, and LRP to accelerate their endocytosis, with these activities validated in transgenic and null mouse models of amyloid and tau pathology [PMID:22361682, PMID:23348590, PMID:19251705, PMID:25741591, PMID:29016855]. In dendritic cells, RANBP9 bridges AXL and LRP-1 to mediate efferocytosis and antigen cross-presentation [PMID:24509082]. RANBP9 is essential for mammalian gametogenesis, with null mice of both sexes sterile due to meiotic arrest and premature ovarian failure [PMID:21561988].","teleology":[{"year":1998,"claim":"Established the first molecular identity of RanBPM as a Ran-GTP-binding protein with a proposed role in microtubule nucleation, anchoring it to the centrosomal/cytoskeletal compartment.","evidence":"Yeast two-hybrid with Ran bait, fractionation, and antibody inhibition of aster formation","pmids":["9817760"],"confidence":"Medium","gaps":["Based on a truncated isoform later shown not to be centrosomal","Catalytic mechanism of microtubule nucleation not defined"]},{"year":2001,"claim":"Corrected the protein model by showing the authentic full-length protein is 90 kDa, forms a >670 kDa complex, and localizes to nucleus and perinuclear cytoplasm rather than the centrosome itself.","evidence":"Full-length cDNA cloning, multi-epitope immunoblotting, gel filtration, and immunofluorescence","pmids":["11470507"],"confidence":"High","gaps":["Identity of the >670 kDa complex partners not yet defined","Functional consequence of nuclear vs cytoplasmic pools unresolved"]},{"year":2002,"claim":"Defined RANBP9 as a SPRY-domain adaptor that couples the MET receptor to Ras-ERK signaling and as a regulator of nuclear receptors, establishing its role in receptor-driven transcription.","evidence":"Y2H, GST pull-down, Co-IP, Ras-GTP loading and ERK/SRE reporter assays for MET; reciprocal pull-down and reporter assays for AR/GR","pmids":["12147692","12361945"],"confidence":"High","gaps":["Whether the same SPRY surface mediates both kinase and receptor binding not resolved","Endogenous physiological relevance of nuclear receptor coactivation beyond overexpression unclear"]},{"year":2002,"claim":"Showed RANBP9 is itself a proteasome substrate whose stability is set by USP11 deubiquitination, framing it as a tightly turned-over scaffold.","evidence":"Y2H, Co-IP, pulse-chase with proteasome inhibitors, and in vitro/in vivo ubiquitination with recombinant USP11","pmids":["12084015"],"confidence":"High","gaps":["E3 ligase ubiquitinating RANBP9 not identified","Signals that regulate USP11 engagement unknown"]},{"year":2003,"claim":"Identified the core LisH-CTLH module shared by RanBPM, Twa1, and Muskelin, providing the first evidence of a defined RANBP9-containing protein assembly.","evidence":"Y2H, reciprocal Co-IP, and gel-filtration chromatography","pmids":["12559565"],"confidence":"Medium","gaps":["Full composition and enzymatic activity of the assembly not yet defined","Stoichiometry and architecture unknown"]},{"year":2007,"claim":"Defined the full CTLH complex composition, establishing RANBP9 as a stable subunit of a large multiprotein assembly rather than a free adaptor.","evidence":"Anti-RanBPM IP-tandem MS from HEK293, Co-IP, and in vitro Twa1 pull-down across components","pmids":["17467196"],"confidence":"High","gaps":["Catalytic/E3 activity of the complex not demonstrated at this stage","Substrate repertoire unknown"]},{"year":2009,"claim":"Linked RANBP9 to amyloidogenesis by showing its N-terminal SPRY-LisH module scaffolds APP, BACE1, and LRP to accelerate APP endocytosis and Abeta production.","evidence":"Co-IP, surface biotinylation, endocytosis and lipid-raft assays, siRNA knockdown, and Abeta ELISA in CHO cells and primary neurons","pmids":["19251705","19729516"],"confidence":"High","gaps":["Whether CTLH complex E3 activity contributes to APP processing not addressed","Relationship of the stable N60 processed form to physiological signaling unclear"]},{"year":2009,"claim":"Established RANBP9 as a proapoptotic factor that relocalizes from nucleus to cytoplasm after DNA damage and is required for caspase activation and mitochondrial Bax/Bcl-2 balance.","evidence":"Transient expression, siRNA knockdown, caspase assays, relocalization immunofluorescence, and Bax/Bcl-2 western blot after irradiation","pmids":["19996306"],"confidence":"Medium","gaps":["Mechanism of nucleocytoplasmic relocalization not defined here","How SPRY domain negatively regulates apoptosis unclear"]},{"year":2011,"claim":"Demonstrated an essential, cell-autonomous in vivo requirement for RANBP9 in gametogenesis, identifying meiotic prophase I as the critical stage.","evidence":"Mouse knockout with histology, meiotic staging, and chimera experiments using knockout ES cells","pmids":["21561988"],"confidence":"High","gaps":["Molecular pathway through which RANBP9 supports meiotic progression not defined","Relevant germ-cell partners not identified"]},{"year":2012,"claim":"Connected RANBP9 to mitochondrial apoptosis and cytoskeletal regulation by placing cofilin downstream of RANBP9 and showing in vivo amyloid and synaptic phenotypes from RANBP9 dosage.","evidence":"siRNA epistasis for cofilin, cofilin phosphorylation blots, integrin endocytosis/focal-adhesion assays, and transgenic/null mouse Abeta and synaptic protein analyses","pmids":["22361682","22223749","22294787"],"confidence":"High","gaps":["Direct enzyme linking RANBP9 to cofilin dephosphorylation not yet identified","Mechanism coupling integrin trafficking to apoptosis unresolved"]},{"year":2013,"claim":"Showed RANBP9 cooperates with p73 to execute mitochondria-mediated death and is itself stabilized by COPS5, integrating its apoptotic and turnover regulation.","evidence":"Co-IP, bidirectional siRNA epistasis, mitochondrial membrane potential, Bax oligomerization and cytochrome c release assays; COPS5 half-life and Abeta ELISA experiments","pmids":["23348590","23926111"],"confidence":"High","gaps":["How RANBP9 increases p73 transcriptionally not mechanistically resolved","COPS5 mechanism of stabilization (CTLH-dependent or not) unclear"]},{"year":2014,"claim":"Defined RANBP9 as an HDAC6 regulator and an aggresome-forming factor, and established its CTLH/AXL-LRP-1 scaffolding role in dendritic-cell efferocytosis and cross-presentation in vivo.","evidence":"Co-IP with domain deletion, HDAC6 deacetylase assays, shRNA rescue of aggresome formation; in vivo DC-specific deletions, efferocytosis and cross-presentation assays, HSV-1 model","pmids":["24795145","24509082"],"confidence":"High","gaps":["Whether HDAC6 inhibition requires intact CTLH E3 activity not fully resolved here","Direct vs indirect bridging of AXL-LRP-1 mechanistically incomplete"]},{"year":2015,"claim":"Mapped RANBP9 nucleocytoplasmic shuttling determinants and showed CTLH-complex-mediated HDAC6 inhibition restrains migration, plus the SSH1-cofilin axis underlying its neurotoxic activity in vivo.","evidence":"Systematic NLS/NES deletion analysis with fractionation; Co-IP of CTLH members with HDAC6 and migration assays; SSH1-dependent cofilin translocation and APP/PS1 mouse rescue with LTP and behavior","pmids":["25659156","28668087","25741591"],"confidence":"High","gaps":["How DNA damage triggers the NES-dependent shift not defined","Whether SSH1 regulation is direct or via the CTLH complex unclear"]},{"year":2016,"claim":"Solved the SPRY domain structure to define its peptide-binding surface, and established RANBP9 as an ATM substrate that promotes the DNA damage response and supports c-Kit protein stability.","evidence":"X-ray crystallography of apo and DDX4-peptide complex with mutagenesis; ATM phospho-site mapping (S181/S603), nuclear accumulation with ATM inhibition, HR reporter; Co-IP and null-mouse c-Kit protein/mRNA analysis","pmids":["27622290","26943034","27835883"],"confidence":"High","gaps":["How ATM phosphorylation drives nuclear accumulation mechanistically incomplete","Whether SPRY surface mediates all kinase interactions not generalized structurally"]},{"year":2023,"claim":"Defined the molecular basis of RANBP9's DDR function by showing it stabilizes p21 through USP11 recruitment in a p53-independent manner.","evidence":"Co-IP of RanBP9-p21-USP11, in vivo ubiquitylation assay, overexpression/silencing, and ATM-dependent nuclear translocation with DDR readouts","pmids":["37676377"],"confidence":"Medium","gaps":["Whether p21 stabilization involves the CTLH complex not addressed","Single-lab finding without reciprocal in vivo validation"]},{"year":2025,"claim":"Revealed tissue- and tag-specific RANBP9 interactomes and paralog interplay, showing RANBP9 and RANBP10 independently nucleate the CTLH complex and antagonistically tune its ubiquitylation output.","evidence":"In vivo TurnX knock-in macrophage proteomics with tag-switching control; inducible NSCLC overexpression/loss-of-function with proteomics and ubiquitylome profiling and patient lysates","pmids":["40223093","40883813"],"confidence":"Medium","gaps":["Substrates uniquely specified by RANBP9 vs RANBP10 not fully defined","Functional consequences of macrophage-specific interactions not validated"]},{"year":null,"claim":"The direct substrate repertoire of the RANBP9-containing CTLH E3 ligase and how RANBP9's scaffolding choices are selected across tissues and signaling states remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined catalytic ubiquitination substrate set attributable specifically to RANBP9","Rules governing partner selection among receptors, DDR factors, and apoptotic effectors unknown","Structural basis for assembly into the full CTLH complex not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,26,44,52]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[19,56]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[43,46,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,47,49]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,9,47]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[47,46]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[47]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[49,54]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[28,39,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,31,38]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,19,56]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[44]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[26,45,48]}],"complexes":["CTLH complex"],"partners":["MUSKELIN","USP11","HDAC6","AXL","LRP1","MET","COPS5","CDKN1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96S59","full_name":"Ran-binding protein 9","aliases":["BPM-L","BPM90","Ran-binding protein M","RanBPM","RanBP7"],"length_aa":729,"mass_kda":77.8,"function":"May act as scaffolding protein, and as adapter protein to couple membrane receptors to intracellular signaling pathways (Probable). Acts as a mediator of cell spreading and actin cytoskeleton rearrangement (PubMed:18710924). Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). May be involved in signaling of ITGB2/LFA-1 and other integrins (PubMed:14722085). Enhances HGF-MET signaling by recruiting Sos and activating the Ras pathway (PubMed:12147692). Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but not affect estrogen-induced transactivation (PubMed:12361945, PubMed:18222118). Stabilizes TP73 isoform Alpha, probably by inhibiting its ubiquitination, and increases its proapoptotic activity (PubMed:15558019). Inhibits the kinase activity of DYRK1A and DYRK1B. Inhibits FMR1 binding to RNA","subcellular_location":"Cytoplasm; Nucleus; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96S59/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RANBP9","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":1208,"dependency_fraction":0.04718543046357616},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000010017","cell_line_id":"CID001574","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"RANBP10","stoichiometry":10.0},{"gene":"MAEA","stoichiometry":10.0},{"gene":"WDR26","stoichiometry":10.0},{"gene":"MKLN1","stoichiometry":10.0},{"gene":"GID8","stoichiometry":10.0},{"gene":"GID4","stoichiometry":10.0},{"gene":"ARMC8","stoichiometry":10.0},{"gene":"RMND5A","stoichiometry":4.0},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"YPEL5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001574","total_profiled":1310},"omim":[{"mim_id":"620893","title":"IMPORTIN 9; IPO9","url":"https://www.omim.org/entry/620893"},{"mim_id":"618964","title":"REQUIRED FOR MEIOTIC NUCLEAR DIVISION 5 HOMOLOG A; RMND5A","url":"https://www.omim.org/entry/618964"},{"mim_id":"618521","title":"ARMADILLO REPEAT-CONTAINING PROTEIN 8; ARMC8","url":"https://www.omim.org/entry/618521"},{"mim_id":"614031","title":"RAN-BINDING PROTEIN 10; RANBP10","url":"https://www.omim.org/entry/614031"},{"mim_id":"613394","title":"MICRO RNA 138-1; MIR138-1","url":"https://www.omim.org/entry/613394"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RANBP9"},"hgnc":{"alias_symbol":["RanBPM"],"prev_symbol":[]},"alphafold":{"accession":"Q96S59","domains":[{"cath_id":"2.60.120.920","chopping":"144-353","consensus_level":"high","plddt":97.5223,"start":144,"end":353},{"cath_id":"-","chopping":"362-463_609-719","consensus_level":"medium","plddt":91.8672,"start":362,"end":719}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96S59","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96S59-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96S59-F1-predicted_aligned_error_v6.png","plddt_mean":72.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RANBP9","jax_strain_url":"https://www.jax.org/strain/search?query=RANBP9"},"sequence":{"accession":"Q96S59","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96S59.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96S59/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96S59"}},"corpus_meta":[{"pmid":"9817760","id":"PMC_9817760","title":"When overexpressed, a novel centrosomal protein, RanBPM, causes ectopic microtubule nucleation similar to gamma-tubulin.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9817760","citation_count":165,"is_preprint":false},{"pmid":"12147692","id":"PMC_12147692","title":"Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12147692","citation_count":127,"is_preprint":false},{"pmid":"17467196","id":"PMC_17467196","title":"RanBPM, Muskelin, p48EMLP, p44CTLH, and the armadillo-repeat proteins ARMC8alpha and ARMC8beta are components of the CTLH complex.","date":"2007","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17467196","citation_count":106,"is_preprint":false},{"pmid":"24509082","id":"PMC_24509082","title":"An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24509082","citation_count":101,"is_preprint":false},{"pmid":"11470507","id":"PMC_11470507","title":"Full-sized RanBPM cDNA encodes a protein possessing a long stretch of proline and glutamine within the N-terminal region, comprising a large protein complex.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11470507","citation_count":97,"is_preprint":false},{"pmid":"14722085","id":"PMC_14722085","title":"RanBPM is a phosphoprotein that associates with the plasma membrane and interacts with the integrin LFA-1.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14722085","citation_count":83,"is_preprint":false},{"pmid":"12361945","id":"PMC_12361945","title":"RanBPM, a nuclear protein that interacts with and regulates transcriptional activity of androgen receptor and glucocorticoid 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Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28547582","citation_count":3,"is_preprint":false},{"pmid":"40883813","id":"PMC_40883813","title":"RANBP9 and RANBP10 cooperate in regulating non-small cell lung cancer proliferation.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40883813","citation_count":2,"is_preprint":false},{"pmid":"29067546","id":"PMC_29067546","title":"1H, 13C and 15N chemical shift assignment of lissencephaly-1 homology (LisH) domain homodimer of human two-hybrid-associated protein 1 with RanBPM (Twa1).","date":"2017","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/29067546","citation_count":2,"is_preprint":false},{"pmid":"18318119","id":"PMC_18318119","title":"[Multiadaptor 4.1 and RanBP9 protein family members as putative interaction partners for VARP, a Rab21 GTPase guanine nucleotide exchange factor].","date":"2007","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/18318119","citation_count":1,"is_preprint":false},{"pmid":"38826292","id":"PMC_38826292","title":"An in vivo \"turning model\" reveals new RanBP9 interactions in lung macrophages.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38826292","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48999,"output_tokens":13796,"usd":0.176969,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25469,"output_tokens":5805,"usd":0.136235,"stage2_stop_reason":"end_turn"},"total_usd":0.313204,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"RanBPM (RanBP9) was identified as a centrosomal protein that binds GTP-Ran and is required for microtubule nucleation; overexpression produced ectopic microtubule nucleation sites co-localizing with gamma-tubulin, and anti-RanBPM antibodies inhibited microtubule aster formation.\",\n      \"method\": \"Yeast two-hybrid (Ran bait), sucrose-density gradient centrifugation, immunofluorescence, antibody inhibition assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, fractionation, antibody inhibition) in single lab; centrosomal localization later revised by full-length cDNA study\",\n      \"pmids\": [\"9817760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The originally described 55 kDa RanBPM was a truncated isoform; the full-length protein is 90 kDa with an N-terminal proline/glutamine-rich region, forms a >670 kDa complex, and localizes predominantly to nucleus and cytoplasm surrounding the centrosome—not within the centrosome itself.\",\n      \"method\": \"Full-length cDNA cloning, immunoblotting with antibodies against three distinct regions, gel filtration, immunofluorescence\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct molecular characterization with multiple antibodies and size-exclusion; revised prior model with rigorous controls\",\n      \"pmids\": [\"11470507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RanBPM interacts with the tyrosine kinase domain of MET receptor via its SPRY domain; RanBPM activates the Ras-Erk-SRE pathway by recruiting Sos to the MET complex, functioning as an adaptor protein.\",\n      \"method\": \"Yeast two-hybrid, in vitro GST pull-down, co-immunoprecipitation, Ras-GTP loading assay, ERK phosphorylation assay, SRE-luciferase reporter, cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, GST pull-down, Co-IP, functional reporter, migration assay) in single rigorous study\",\n      \"pmids\": [\"12147692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RanBPM interacts with androgen receptor (AR) and glucocorticoid receptor (GR), but not estrogen receptor, and enhances their transcriptional activity in a ligand-dependent manner when overexpressed in prostate cancer cells.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, His-tag pull-down, transient overexpression with luciferase reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down plus functional reporter, single lab\",\n      \"pmids\": [\"12361945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"USP11, a ubiquitin-specific protease, interacts with RanBPM and deubiquitinates it; RanBPM undergoes proteasome-dependent degradation and is ubiquitinated in vivo and in vitro, and USP11 inhibits this ubiquitination in a dose-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, pulse-chase analysis with proteasome inhibitors, in vivo and in vitro ubiquitination assays, recombinant USP11 inhibition assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay plus in vivo co-IP, pulse-chase, and enzymatic inhibition providing multiple orthogonal methods\",\n      \"pmids\": [\"12084015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HIPK2 (homeodomain-interacting protein kinase 2) interacts with RanBPM in the nucleus of mammalian cells; both wild-type HIPK2 and a kinase-dead HIPK2 mutant co-localize with RanBPM in defined nuclear structures.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, immunofluorescence co-localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-IP plus co-localization only, no functional consequence established\",\n      \"pmids\": [\"12220523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RanBPM forms a protein complex with Twa1 and Muskelin (hMuskelin), as demonstrated by co-immunoprecipitation and gel-filtration analysis; all three proteins share the LisH-CTLH motif.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, gel-filtration chromatography\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus gel filtration, single lab\",\n      \"pmids\": [\"12559565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RanBPM interacts with the death domain of p75NTR neurotrophin receptor intracellular domain.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP with domain mapping, no downstream functional readout\",\n      \"pmids\": [\"12963025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CDK11(p46), a caspase-processed apoptotic kinase, directly interacts with RanBPM via its SPRY domain and phosphorylates RanBPM in vitro.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation in human cells, in vitro kinase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus Co-IP, single lab\",\n      \"pmids\": [\"14511641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RanBPM is a peripheral plasma membrane protein that interacts with the cytoplasmic domain of integrin LFA-1 (beta2) and beta1 integrin via in vitro and in vivo assays; RanBPM is phosphorylated on serine residues and this phosphorylation is regulated by p38 kinase activity; RanBPM synergizes with LFA-1 in AP-1-dependent transcriptional activation.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, membrane fractionation, phosphorylation assays with p38 inhibitor SB203580, luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including membrane fractionation, Co-IP, phosphorylation analysis, and functional reporter in single rigorous study\",\n      \"pmids\": [\"14722085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RanBPM interacts with the tyrosine kinase domain of Axl and Sky/Tyro3 receptor tyrosine kinases via its SPRY-LisH domain region; a truncated RanBPM lacking this region fails to interact with Axl; endogenous Axl and RanBPM interact constitutively in multiple mammalian cell lines.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in cell-free and mammalian cell systems, domain deletion analysis, Gas6 stimulation experiment\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and endogenous interaction confirmed, single lab\",\n      \"pmids\": [\"15964779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse RanBPM interacts with the germline-specific RNA helicase MVH (mouse vasa homolog) in testicular germ cells; both proteins associate with perinuclear RNA-protein complexes and chromatoid bodies.\",\n      \"method\": \"Yeast two-hybrid, co-localization by immunofluorescence in testis\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Y2H plus co-localization only, no biochemical confirmation of direct interaction in vivo\",\n      \"pmids\": [\"14648869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RanBPM interacts with p73alpha (but not p53) through the extreme C-terminal region of p73alpha; RanBPM stabilizes p73alpha by inhibiting its ubiquitination, thereby prolonging its half-life and enhancing its proapoptotic activity; co-expression causes nuclear co-localization of RanBPM and p73alpha.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunofluorescence, ubiquitination assay, half-life analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and half-life analysis in single lab\",\n      \"pmids\": [\"15558019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RanBPM interacts with the cytoplasmic domain of neural cell adhesion molecule L1 via its N-terminal SPRY domain; overexpression of N-RanBPM reduces L1-triggered ERK1/2 activation by 50% and inhibits L1-mediated neurite outgrowth and branching.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, L1 antibody patching/subcellular redistribution, ERK activation assay, primary neuron morphology\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down, Co-IP, and functional ERK/neurite assays, single lab\",\n      \"pmids\": [\"16000162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RanBPM interacts with TAF4 (a TFIID subunit); co-transfection of TAF4 and RanBPM increases primary neurite processes in neural progenitors; the effect is abolished by a TAF4 isoform lacking the RanBPM-interacting domain.\",\n      \"method\": \"Protein-protein interaction screen, co-immunoprecipitation from neural stem cell extracts, co-transfection/morphology assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP plus functional morphology assay, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"15911349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RanBPM associates with the N-terminus of CD39/ecto-NTPDase1; co-expression of RanBPM substantially reduces NTPDase activity of recombinant CD39 but not of an N-terminus-deleted CD39 mutant, demonstrating functional regulation of ecto-nucleotidase activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in transfected mammalian cells, NTPDase activity assay, domain deletion mutant analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay with mutant validation plus Co-IP, single lab\",\n      \"pmids\": [\"16478441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RanBPM physically interacts with Plexin-A1 and mediates Semaphorin3A signaling; overexpression of RanBPM with Plexin-A1 reduces cell spreading and inhibits axonal outgrowth in vitro and in vivo; a truncated RanBPM blocks Sema3A responsiveness; RanBPM knockdown reduces Sema3A responsiveness; the RanBPM/Plexin-A1 complex is regulated by MICAL expression.\",\n      \"method\": \"Domain-based interaction screen, co-immunoprecipitation, overexpression and truncation/knockdown functional assays in neurons and non-neuronal cells, in vivo axon guidance assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, multiple gain/loss-of-function experiments, both in vitro and in vivo validation\",\n      \"pmids\": [\"16672672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RanBPM interacts with TrkA via its SPRY motif (binding at TrkA tyrosine kinase domain); overexpression of RanBPM inhibits NGF-induced NFAT-dependent luciferase expression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, NFAT-luciferase reporter assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and GST pull-down plus single functional reporter assay, single lab\",\n      \"pmids\": [\"16959415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RanBPM is a coactivator of thyroid hormone receptors (TRs); it binds TRs in a ligand-independent manner via its C-terminal region interacting with the TR DNA-binding domain; overexpression enhances TR-dependent transcriptional activation, whereas the truncated RanBPM55 lacking the N-terminal polyglutaminated region inhibits it in a dominant-negative manner.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, transient transfection luciferase reporter, domain deletion competition assays\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down, Co-IP, and functional luciferase assays with deletion analysis, single lab\",\n      \"pmids\": [\"16595702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RanBPM is a component of a large protein complex (renamed CTLH complex) composed of Muskelin, p48EMLP, p44CTLH, ARMC8alpha, and ARMC8beta; each component was confirmed by co-immunoprecipitation and in vitro Twa1 pull-down.\",\n      \"method\": \"Tandem MS with anti-RanBPM antibody immunoprecipitation from HEK293 cells, co-immunoprecipitation in Cos-7 cells, in vitro pull-down with bacterially expressed Twa1\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mass spectrometry identification confirmed by independent Co-IP and in vitro pull-down across multiple components\",\n      \"pmids\": [\"17467196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Muskelin subcellular localization is co-regulated with RanBP9; knockdown of muskelin or RanBP9 both produce protrusive cell morphologies with enlarged cell perimeters; RanBP9 binding via the muskelin C-terminus is required to restore normal morphology, identifying a muskelin-RanBP9 complex as a nucleocytoplasmic mediator of cell morphology.\",\n      \"method\": \"Subcellular fractionation, siRNA knockdown, rescue with cDNA variants, cell morphology quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with rescue, subcellular fractionation, multiple cDNA variants tested; single lab\",\n      \"pmids\": [\"18710924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RanBPM interacts with metabotropic glutamate receptors mGlu2 and other group II and group III receptors (except mGlu6) in the retina, co-localizing with mGlu8b in the inner plexiform layer.\",\n      \"method\": \"Yeast two-hybrid (mGlu8 bait), co-immunoprecipitation, immunofluorescence co-localization in retina sections\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Y2H plus Co-IP and co-localization, no functional downstream assay, single lab\",\n      \"pmids\": [\"18555800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RanBPM interacts with p42(IP4)/Centaurin-alpha-1 via its SPRY domain; D-Ins(1,3,4,5)P4 (a specific ligand for p42(IP4)) inhibits this interaction in a concentration-dependent and stereoselective manner.\",\n      \"method\": \"Co-immunoprecipitation with endogenous RanBPM from rat brain, in vitro binding assay, inositol phosphate competition assay, domain mapping with SPRY domain\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous Co-IP from brain plus in vitro ligand competition, single lab\",\n      \"pmids\": [\"18298663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RanBPM interacts with Rta (EBV immediate-early protein) via the SPRY domain of RanBPM; this interaction promotes Rta transactivation activity, and mechanistically RanBPM interacts with SUMO-E2 (Ubc9) to enhance sumoylation of Rta by SUMO-1.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal co-localization, transient transfection reporter assay, sumoylation assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, sumoylation assay, reporter assay; single lab; functional mechanism proposed through sumoylation\",\n      \"pmids\": [\"18455188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RanBPM modulates T-type Ca2+ channel Cav3.1 by binding its intracellular loop between transmembrane domains I and II; RanBPM expression increases Cav3.1 currents and abolishes PKC activator-mediated inhibition of these currents.\",\n      \"method\": \"Yeast two-hybrid, whole-cell patch-clamp electrophysiology, domain binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — electrophysiology with domain-level interaction mapping, single lab\",\n      \"pmids\": [\"18801335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila RanBPM is required for normal germline stem cell (GSC) niche organization; loss of the long RanBPM isoform causes defects in niche cell size, niche organization, and abnormal accumulation of adherens junction component Armadillo (beta-catenin), increasing GSC attachment to niche cap cells.\",\n      \"method\": \"Drosophila genetics (null and isoform-specific alleles), mosaic analysis, immunofluorescence for Armadillo and Hts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with molecular marker analysis, Drosophila model\",\n      \"pmids\": [\"18762575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RanBPM promotes BACE1 cleavage of APP and Abeta generation; RanBP9 N-terminal SPRY-LisH domain interacts with LRP, APP, and BACE1 simultaneously, scaffolding these proteins together; RanBP9 reduces cell surface APP, accelerates APP internalization, and increases lipid raft association of APP; knockdown of endogenous RanBP9 significantly reduces Abeta generation in CHO cells and primary neurons.\",\n      \"method\": \"Co-immunoprecipitation, cell surface biotinylation, endocytosis assay, lipid raft fractionation, siRNA knockdown, Abeta ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including endocytosis assay, raft fractionation, knockdown in primary neurons, replicated across cell types\",\n      \"pmids\": [\"19251705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A processed form of RanBP9 (RanBP9-N60, residues 1-392) lacks a nuclear localization signal, displays enhanced cytoplasmic localization and >3-fold enhanced stability compared to full-length RanBP9, retains capacity to form self-interacting multimeric complexes via LisH domain, and potentiates Abeta generation ~5-fold.\",\n      \"method\": \"Deletion mutant analysis, subcellular fractionation, protein stability assays, Abeta ELISA\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutant characterization with functional readout, single lab\",\n      \"pmids\": [\"19729516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RanBPM has proapoptotic activity: transient expression induces caspase activation; the C-terminal domain stimulates this activity while the central SPRY domain negatively regulates it; RanBPM knockdown prevents DNA damage-induced caspase-3 and caspase-2 activation; following ionizing radiation, RanBPM relocalizes from nucleus to cytoplasm; RanBP9 downregulation decreases mitochondria-associated Bax and increases Bcl-2.\",\n      \"method\": \"Transient expression, siRNA knockdown, caspase activation assay, immunofluorescence for relocalization, Bax/Bcl-2 western blot\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain analysis, siRNA knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"19996306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RanBPM interacts with acetylcholinesterase (AChE) C-terminal domain and translocates from the cytoplasm to the nucleus during cisplatin-induced apoptosis, similar to AChE.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunoblotting of cytoplasmic and nuclear fractions\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and fractionation, single lab, limited functional follow-up\",\n      \"pmids\": [\"19902122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RanBPM interacts with citron kinase (CITK) at adherens junctions of the neocortical ventricular surface; RanBPM knockdown decreases CITK polarization to the ventricular surface, increases mitotic cells, and decreases cytokinetic cells; the CITK mutation rescues the RanBPM knockdown mitosis phenotype, placing RanBPM upstream of CITK in M-phase progression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, protein overlay, in utero RNAi, genetic epistasis with CITK mutant\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus Co-IP and in vivo RNAi, single lab\",\n      \"pmids\": [\"19790105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RanBPM interacts with TrkB receptor and contributes to BDNF-induced MAPK and Akt activation; RanBPM overexpression enhances BDNF-induced MAPK/Akt signaling; RanBPM siRNA knockdown has opposite effects; RanBPM promotes BDNF-induced hippocampal neuronal morphogenesis and BDNF-mediated survival.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and siRNA knockdown, phospho-MAPK/Akt western blot, neuronal morphology and survival assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with multiple readouts, single lab\",\n      \"pmids\": [\"20403074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RanBPM interacts with YPEL5 protein; RanBPM was identified as a YPEL5-binding protein and their interaction was confirmed by yeast two-hybrid.\",\n      \"method\": \"Yeast two-hybrid\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — Y2H only, no biochemical confirmation or functional consequence for RanBPM specifically\",\n      \"pmids\": [\"20580816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RanBPM interacts with Mgl-1 (mammalian Lgl1); RanBPM inhibits Mgl-1 proteasomal degradation and extends its half-life; RanBPM enhances Mgl-1 activity in cell migration and colony formation assays.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, protein stability assay, cell migration and colony formation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, GST pull-down, stability assay, functional assays; single lab\",\n      \"pmids\": [\"20829363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RanBPM is essential for mammalian gametogenesis: RanBPM-null mice of both sexes are sterile; males show spermatogenesis arrest at late pachytene-diplotene prophase I without chromosome synapsis defects; females show premature ovarian failure at prophase I; chimera experiments demonstrate cell-autonomous function in germ cells.\",\n      \"method\": \"Gene knockout in mice, histological analysis, meiotic staging, chimeric mouse generation with knockout ES cells\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout phenotype with mechanistic stage determination, cell-autonomous demonstration via chimeras\",\n      \"pmids\": [\"21561988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RanBP9 overexpression disrupts integrin-dependent cell attachment, spreading, and focal adhesion signaling (Pyk2/paxillin), while knockdown promotes these processes; RanBP9 accelerates endocytosis of β1-integrin, LRP, and APP; primary hippocampal neurons from RanBP9-transgenic mice show reduced surface β1-integrin, LRP, APP, and neurite arborization.\",\n      \"method\": \"Cell attachment/spreading assays, focal adhesion immunostaining, cell surface biotinylation, endocytosis assay, siRNA knockdown, primary neuron from transgenic mice\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays with both gain and loss of function, in vitro and in vivo validation\",\n      \"pmids\": [\"22223749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RanBP9 activates/dephosphorylates cofilin and promotes Abeta-induced apoptosis; siRNA knockdown of cofilin abolishes both Abeta- and RanBP9-induced apoptosis, placing cofilin downstream of RanBP9 in the apoptotic pathway.\",\n      \"method\": \"siRNA knockdown (cofilin, RanBP9), cofilin phosphorylation western blot, apoptosis assays (RanBP9-Tg mice), spatial memory testing\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via siRNA, in vivo transgenic model, multiple readouts; single lab\",\n      \"pmids\": [\"22361682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RanBP9 overexpression in mice leads to >2-fold increase in Abeta40 and Abeta42 levels and increased amyloid plaque deposition; RanBP9-null mice show increased synaptic protein levels (synaptophysin, PSD-95, drebrin A).\",\n      \"method\": \"Transgenic and null mouse generation, ELISA for Abeta, amyloid plaque immunostaining, synaptic protein western blot\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic and null mouse models with multiple biochemical readouts confirming bidirectional regulation\",\n      \"pmids\": [\"22294787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RanBPM inhibits ERK signaling by forming a complex with c-Raf, decreasing Hsp90 binding to c-Raf, and destabilizing c-Raf protein; RanBPM knockdown stimulates MEK and ERK phosphorylation leading to Bcl-2 upregulation; RanBPM expression prevents MEK/ERK activation by active RasV12 and active c-Raf.\",\n      \"method\": \"Co-immunoprecipitation (RanBPM-c-Raf complex), Hsp90 binding assay, siRNA/shRNA knockdown, ERK phosphorylation assay, Bcl-2 western blot, cell proliferation and migration assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with multiple functional downstream readouts, single lab; mechanism via Hsp90 displacement from c-Raf\",\n      \"pmids\": [\"23118896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RanBP9 physically interacts with tumor suppressor p73, increases endogenous p73alpha levels at both transcriptional and post-translational levels, and cooperates with p73 to induce mitochondria-mediated cell death (loss of mitochondrial membrane potential, Bax oligomerization, cytochrome c release); RanBP9 knockdown suppresses p73-induced apoptosis and vice versa.\",\n      \"method\": \"Co-immunoprecipitation, p73 western blot (transcriptional and stability analysis), siRNA knockdown of p73 and RanBP9, mitochondrial membrane potential assay, Bax oligomerization, cytochrome c release, Mdivi-1/Bcl-2/Bcl-xl inhibitor experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional siRNA epistasis, Co-IP, and multiple orthogonal mitochondrial assays in single rigorous study\",\n      \"pmids\": [\"23348590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RanBP9 potentiates Abeta-induced ROS overproduction, apoptosis, and calcium deregulation in hippocampal neurons; RanBP9 selectively delays cytosolic Ca2+ clearance by the mitochondrial calcium uniporter through cofilin translocation to mitochondria; RanBP9 retards anterograde axonal transport of mitochondria and decreases synaptic mitochondrial activity.\",\n      \"method\": \"Primary hippocampal neuron overexpression, ROS assay, Ca2+ imaging, mitochondrial calcium uniporter blockade, cofilin mitochondrial translocation assay, axonal transport live imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in primary neurons, single lab, mechanistic link through cofilin\",\n      \"pmids\": [\"23982146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COPS5 (Jab1/CSN5) is a novel RanBP9-interacting protein that stabilizes RanBP9 protein levels, thereby increasing Abeta generation; COPS5 increases RanBP9 half-life; COPS5 knockdown reduces Abeta generation.\",\n      \"method\": \"Yeast two-hybrid (human brain library), co-immunoprecipitation in neuronal and non-neuronal cells and mouse brain, protein half-life assay, siRNA knockdown, Abeta ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in multiple systems, half-life assay, siRNA knockdown with Abeta readout; single lab\",\n      \"pmids\": [\"23926111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RanBPM interacts with TRAF6 via its SPRY motif; RanBPM inhibits TRAF6 ubiquitination and suppresses TRAF6-triggered NF-κB signaling; RanBPM also blocks TGF-β-induced TβRI nuclear accumulation by competing with TRAF6 for TβRI binding.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal microscopy, FRET, ubiquitination assay, NF-κB reporter assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus Co-IP, ubiquitination assay, and functional reporter; single lab\",\n      \"pmids\": [\"24103590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RanBPM promotes aggresome formation: ionizing radiation and proteasome inhibition cause RanBPM redistribution into perinuclear aggresomes with ubiquitin, dynein, and HDAC6; aggresome formation by HDAC6 is markedly impaired in RanBPM shRNA cells but restored by RanBPM re-expression; RanBPM interacts with HDAC6 via its LisH/CTLH domain and inhibits HDAC6 deacetylase activity.\",\n      \"method\": \"Immunofluorescence for aggresome markers, shRNA knockdown with rescue, co-immunoprecipitation (RanBPM-HDAC6), deacetylase activity assay, LisH/CTLH deletion mutant analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with domain deletion, enzymatic activity assay, shRNA rescue, multiple orthogonal methods\",\n      \"pmids\": [\"24795145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AXL, LRP-1, and RANBP9 form a multiprotein complex mediating DC efferocytosis; AXL binds apoptotic cells but requires LRP-1 for internalization; RANBP9 bridges AXL and LRP-1 (which do not interact directly) to form the complex; this complex is required for DC antigen cross-presentation to CD8+ T cells; mice lacking DC-specific LRP-1, AXL, or RANBP9 show increased AC accumulation and defective viral antigen-specific T cell responses.\",\n      \"method\": \"Targeted genetic deletion in mice, spleen efferocytosis assay, co-immunoprecipitation (AXL-RANBP9-LRP1), DC-T cell coculture cross-presentation assay, HSV-1 infection model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic deletion, Co-IP defining complex, functional efferocytosis and cross-presentation readouts, infection model validation\",\n      \"pmids\": [\"24509082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RanBP9 physically interacts with tau and Hsp90/Hsc70 chaperone complexes; RanBP9 overexpression or knockdown directly increases or reduces tau levels in vitro and in vivo; RanBP9 enhances Hsp90 and Hsc70 ATPase activities; genetic reduction of RanBP9 ameliorates tauopathy in Tau-P301S mice.\",\n      \"method\": \"Co-immunoprecipitation (RanBP9-tau-Hsp90/Hsc70), in vitro ATPase assay, RanBP9 overexpression/knockdown western blot, Tau-P301S mouse model genetic reduction\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ATPase assay, Co-IP, in vivo mouse model, bidirectional regulation confirmed across multiple systems\",\n      \"pmids\": [\"29016855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RanBP9 interacts with HDAC6 and, together with the CTLH complex (via Twa1 and MAEA), inhibits HDAC6 deacetylase activity toward alpha-tubulin; RanBPM associates with microtubules in an HDAC6-dependent manner; RanBPM knockdown-induced increase in cell migration is due to relief of HDAC6 inhibition.\",\n      \"method\": \"Co-immunoprecipitation of HDAC6 with CTLH complex members, acetylated alpha-tubulin western blot, confocal microscopy, shRNA knockdown of multiple CTLH members, wound-healing migration assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of multiple complex members, functional deacetylase readout, migration rescue; single lab\",\n      \"pmids\": [\"28668087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RanBPM contains two distinct nuclear localization motifs (N-terminal proline/glutamine-rich region dominant; C-terminal contributes minimally), one nuclear export signal (NES) whose mutation prevents cytoplasmic accumulation, and its cytoplasmic localization is also conferred by protein-protein interactions; in the cytoplasm, RanBPM partially co-localizes with and associates with alpha-tubulin; in the nucleus, RanBPM is associated with chromatin.\",\n      \"method\": \"Systematic deletion mutant analysis in RanBPM shRNA background, confocal microscopy, microtubule co-localization, chromatin fractionation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain analysis with multiple subcellular localization readouts and biochemical fractionation; single lab\",\n      \"pmids\": [\"25659156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endogenous RanBP9 mediates Abeta-induced cofilin translocation to mitochondria via Slingshot homolog 1 (SSH1); RanBP9 positively regulates SSH1 levels; RanBP9 reduction in APP/PS1 mice protects against cofilin-actin pathology, synaptic damage, gliosis, and Abeta accumulation; RanBP9 reduction significantly enhances LTP and partially rescues contextual memory deficits.\",\n      \"method\": \"siRNA knockdown, primary neuron cofilin translocation assay, in vivo APP/PS1 mouse RanBP9 reduction, LTP electrophysiology, behavioral memory testing\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic reduction with mechanistic (SSH1-cofilin pathway) and functional (LTP, behavior) readouts, replicated in cell and mouse models\",\n      \"pmids\": [\"25741591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ran Binding Protein 9 (RanBP9) is phosphorylated by active ATM on at least S181 and S603 in response to ionizing radiation; DNA damage promotes RanBP9 nuclear accumulation in an ATM-dependent manner; RanBP9 silencing causes delayed activation of ATM, Chk2, γH2AX, and p53, and reduces homologous recombination efficiency, leading to enhanced IR-induced senescence and apoptosis.\",\n      \"method\": \"ATM phosphorylation site identification (S181/S603), ATM inhibition experiments, nuclear accumulation assay, RanBP9 stable silencing in multiple cell lines, ATM/Chk2/γH2AX western blot, homologous recombination reporter assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identified phosphorylation sites, ATM inhibition rescue of localization, multiple DDR readouts replicated across three cell lines\",\n      \"pmids\": [\"26943034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RanBPM/RanBP9 scaffold protein binds c-Kit receptor tyrosine kinase and is required for normal c-Kit protein expression in mouse testis and hematopoietic lineages; RanBPM deletion reduces c-Kit protein but not mRNA, indicating post-translational regulation; this regulation is specific to c-Kit among membrane proteins examined.\",\n      \"method\": \"Co-immunoprecipitation (RanBPM-c-Kit), western blot (protein vs mRNA comparison), RanBPM-null mice phenotypic analysis, human cell line endogenous expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo null mouse phenotype with mRNA/protein dissociation, single lab\",\n      \"pmids\": [\"27835883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the IUS-SPRY domain of RanBPM was determined; this domain adopts a beta-sandwich fold with a unique shallow binding surface formed by conserved loops, positive patch, and a tryptophan-lined bottom; a 20-mer peptide of DDX-4 (RNA helicase) binds this surface with KD ~13 µM; mutagenesis studies elucidate the interaction interface.\",\n      \"method\": \"X-ray crystallography of SPRY domain, crystal structure of peptide-domain complex, isothermal titration calorimetry or equivalent binding assay (KD determination), site-directed mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures (apo and complex) with mutagenesis; single lab but Tier 1 method\",\n      \"pmids\": [\"27622290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RanBP9 SPRY domain interacts with TSSC3 PH domain; RanBP9/TSSC3 complex forms a ternary complex with Src, scaffolding their interaction; this suppresses Src and Src-dependent Akt pathway activation, facilitating mitochondrial-associated anoikis and suppressing lung metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation (RanBP9-TSSC3-Src), domain mapping, anoikis assay, Src/Akt phosphorylation western blot, in vivo lung metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ternary complex with domain mapping, functional anoikis and in vivo metastasis assays; single lab\",\n      \"pmids\": [\"28032865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLOCK interacts with RANBP9 (confirmed by yeast two-hybrid and co-immunoprecipitation in mouse testis); RANBP9 previously known to interact with SF3B3 (spliceosome component); CLOCK also interacts with SF3B3; CLOCK binds mRNAs involved in spermatogenesis (demonstrated by RIP-Seq), suggesting CLOCK-RANBP9 involvement in alternative splicing.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mouse testis, RIP-Seq\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP in testis confirming interaction, but downstream splicing mechanism not directly demonstrated for RanBP9\",\n      \"pmids\": [\"29126923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RanBP9 physically interacts with p21 and recruits the deubiquitinase USP11 to maintain p21 protein stability by deubiquitination; RanBP9 silencing decreases p21 protein levels whereas overexpression increases p21 independent of p53 status; DNA damage promotes nuclear translocation of RanBP9 via ATM signaling; RanBP9 regulates DDR in a p21-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (RanBP9-p21-USP11), in vivo ubiquitylation assay, RanBP9 overexpression/silencing, nuclear translocation assay with ATM inhibition, DDR functional assays\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ternary complex, ubiquitylation assay, p53-independent p21 stabilization demonstrated; single lab\",\n      \"pmids\": [\"37676377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In lung macrophages, RanBP9-V5 co-immunoprecipitates known CTLH complex members; however, >90% of the lung RanBP9-associated proteome differs between the two tagged versions (V5 vs HA), revealing macrophage-specific interactions with proteins involved in innate immune response, DNA damage response, metabolism, and mitochondrial function.\",\n      \"method\": \"In vivo knock-in mouse model (RanBP9-TurnX with LysM-Cre), tandem affinity immunoprecipitation with mass spectrometry from lung tissue\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo proteomics with rigorous tag-switching control; single study but novel in vivo approach\",\n      \"pmids\": [\"40223093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RANBP9 and RANBP10 can each independently support CTLH complex formation; acute overexpression of either Scorpin reshapes the NSCLC cell proteome and ubiquitylome; higher RANBP9/RANBP10 ratio is associated with greater cell proliferation; they act as partial antagonists modulating the CTLH complex ubiquitylation output.\",\n      \"method\": \"Inducible overexpression/loss-of-function cell lines, proteomics, ubiquitylome profiling, patient tumor lysate analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics and ubiquitylome with inducible cell lines; single lab but orthogonal mass spectrometry approaches\",\n      \"pmids\": [\"40883813\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RANBP9/RanBPM is a nucleocytoplasmic scaffolding protein that assembles multiprotein complexes through its SPRY and LisH/CTLH domains: it is a core component of the CTLH E3 ubiquitin ligase complex (with Muskelin, Twa1, MAEA, Rmnd5, ARMC8α/β, p48EMLP, and p44CTLH), undergoes ATM-dependent phosphorylation and nuclear translocation after DNA damage where it stabilizes p21 by recruiting USP11, promotes APP/BACE1/LRP scaffolding to drive amyloidogenic processing and β1-integrin/LRP endocytosis, activates cofilin via SSH1 to induce mitochondrial apoptosis, inhibits HDAC6 deacetylase activity to restrain cell migration, bridges AXL and LRP-1 to mediate DC efferocytosis, interacts with and modulates multiple receptor tyrosine kinases (MET, Axl, TrkA, TrkB, c-Kit) and nuclear receptors (AR, GR, TR), is itself subject to proteasomal degradation regulated by USP11 deubiquitination and COPS5-mediated stabilization, and is essential in vivo for gametogenesis in both sexes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RANBP9 (RanBPM) is a nucleocytoplasmic scaffolding protein that assembles multiprotein complexes through its SPRY and LisH/CTLH domains to coordinate receptor signaling, the DNA damage response, protein turnover, and apoptosis [#19, #51, #2]. It is a core subunit of the large (>670 kDa) CTLH E3 ubiquitin ligase complex together with Muskelin, Twa1, p48EMLP, p44CTLH, ARMC8\\u03b1/\\u03b2, and MAEA, and this complex governs HDAC6-dependent \\u03b1-tubulin deacetylation and cell migration [#1, #19, #46]; its paralog RANBP10 can substitute as the complex-organizing subunit, with the two acting as partial antagonists that tune ubiquitylation output and proliferation [#56]. Its \\u03b2-sandwich SPRY domain presents a shallow conserved binding surface that engages diverse partners, including the tyrosine kinase domains of MET, Axl, TrkA, and c-Kit and the RNA helicase DDX4 [#51, #2, #10, #50]; through these interactions RANBP9 acts as an adaptor that recruits Sos to activate Ras-ERK signaling at MET while modulating multiple other receptor and nuclear-receptor outputs [#2, #18]. In the DNA damage response, RANBP9 is phosphorylated by ATM and translocates to the nucleus, where it promotes efficient ATM/Chk2/\\u03b3H2AX activation and homologous recombination and stabilizes p21 by recruiting the deubiquitinase USP11 in a p53-independent manner [#49, #54]; RANBP9 itself is a degradation substrate whose levels are set by USP11 deubiquitination and COPS5-mediated stabilization [#4, #41]. RANBP9 drives mitochondrial apoptosis by activating cofilin via SSH1 and cooperating with p73, and it promotes amyloidogenic APP processing by scaffolding APP, BACE1, and LRP to accelerate their endocytosis, with these activities validated in transgenic and null mouse models of amyloid and tau pathology [#36, #39, #26, #48, #45]. In dendritic cells, RANBP9 bridges AXL and LRP-1 to mediate efferocytosis and antigen cross-presentation [#44]. RANBP9 is essential for mammalian gametogenesis, with null mice of both sexes sterile due to meiotic arrest and premature ovarian failure [#34].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the first molecular identity of RanBPM as a Ran-GTP-binding protein with a proposed role in microtubule nucleation, anchoring it to the centrosomal/cytoskeletal compartment.\",\n      \"evidence\": \"Yeast two-hybrid with Ran bait, fractionation, and antibody inhibition of aster formation\",\n      \"pmids\": [\"9817760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on a truncated isoform later shown not to be centrosomal\", \"Catalytic mechanism of microtubule nucleation not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Corrected the protein model by showing the authentic full-length protein is 90 kDa, forms a >670 kDa complex, and localizes to nucleus and perinuclear cytoplasm rather than the centrosome itself.\",\n      \"evidence\": \"Full-length cDNA cloning, multi-epitope immunoblotting, gel filtration, and immunofluorescence\",\n      \"pmids\": [\"11470507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the >670 kDa complex partners not yet defined\", \"Functional consequence of nuclear vs cytoplasmic pools unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined RANBP9 as a SPRY-domain adaptor that couples the MET receptor to Ras-ERK signaling and as a regulator of nuclear receptors, establishing its role in receptor-driven transcription.\",\n      \"evidence\": \"Y2H, GST pull-down, Co-IP, Ras-GTP loading and ERK/SRE reporter assays for MET; reciprocal pull-down and reporter assays for AR/GR\",\n      \"pmids\": [\"12147692\", \"12361945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same SPRY surface mediates both kinase and receptor binding not resolved\", \"Endogenous physiological relevance of nuclear receptor coactivation beyond overexpression unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed RANBP9 is itself a proteasome substrate whose stability is set by USP11 deubiquitination, framing it as a tightly turned-over scaffold.\",\n      \"evidence\": \"Y2H, Co-IP, pulse-chase with proteasome inhibitors, and in vitro/in vivo ubiquitination with recombinant USP11\",\n      \"pmids\": [\"12084015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase ubiquitinating RANBP9 not identified\", \"Signals that regulate USP11 engagement unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the core LisH-CTLH module shared by RanBPM, Twa1, and Muskelin, providing the first evidence of a defined RANBP9-containing protein assembly.\",\n      \"evidence\": \"Y2H, reciprocal Co-IP, and gel-filtration chromatography\",\n      \"pmids\": [\"12559565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full composition and enzymatic activity of the assembly not yet defined\", \"Stoichiometry and architecture unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the full CTLH complex composition, establishing RANBP9 as a stable subunit of a large multiprotein assembly rather than a free adaptor.\",\n      \"evidence\": \"Anti-RanBPM IP-tandem MS from HEK293, Co-IP, and in vitro Twa1 pull-down across components\",\n      \"pmids\": [\"17467196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic/E3 activity of the complex not demonstrated at this stage\", \"Substrate repertoire unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked RANBP9 to amyloidogenesis by showing its N-terminal SPRY-LisH module scaffolds APP, BACE1, and LRP to accelerate APP endocytosis and Abeta production.\",\n      \"evidence\": \"Co-IP, surface biotinylation, endocytosis and lipid-raft assays, siRNA knockdown, and Abeta ELISA in CHO cells and primary neurons\",\n      \"pmids\": [\"19251705\", \"19729516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CTLH complex E3 activity contributes to APP processing not addressed\", \"Relationship of the stable N60 processed form to physiological signaling unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established RANBP9 as a proapoptotic factor that relocalizes from nucleus to cytoplasm after DNA damage and is required for caspase activation and mitochondrial Bax/Bcl-2 balance.\",\n      \"evidence\": \"Transient expression, siRNA knockdown, caspase assays, relocalization immunofluorescence, and Bax/Bcl-2 western blot after irradiation\",\n      \"pmids\": [\"19996306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nucleocytoplasmic relocalization not defined here\", \"How SPRY domain negatively regulates apoptosis unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated an essential, cell-autonomous in vivo requirement for RANBP9 in gametogenesis, identifying meiotic prophase I as the critical stage.\",\n      \"evidence\": \"Mouse knockout with histology, meiotic staging, and chimera experiments using knockout ES cells\",\n      \"pmids\": [\"21561988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway through which RANBP9 supports meiotic progression not defined\", \"Relevant germ-cell partners not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected RANBP9 to mitochondrial apoptosis and cytoskeletal regulation by placing cofilin downstream of RANBP9 and showing in vivo amyloid and synaptic phenotypes from RANBP9 dosage.\",\n      \"evidence\": \"siRNA epistasis for cofilin, cofilin phosphorylation blots, integrin endocytosis/focal-adhesion assays, and transgenic/null mouse Abeta and synaptic protein analyses\",\n      \"pmids\": [\"22361682\", \"22223749\", \"22294787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzyme linking RANBP9 to cofilin dephosphorylation not yet identified\", \"Mechanism coupling integrin trafficking to apoptosis unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed RANBP9 cooperates with p73 to execute mitochondria-mediated death and is itself stabilized by COPS5, integrating its apoptotic and turnover regulation.\",\n      \"evidence\": \"Co-IP, bidirectional siRNA epistasis, mitochondrial membrane potential, Bax oligomerization and cytochrome c release assays; COPS5 half-life and Abeta ELISA experiments\",\n      \"pmids\": [\"23348590\", \"23926111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RANBP9 increases p73 transcriptionally not mechanistically resolved\", \"COPS5 mechanism of stabilization (CTLH-dependent or not) unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined RANBP9 as an HDAC6 regulator and an aggresome-forming factor, and established its CTLH/AXL-LRP-1 scaffolding role in dendritic-cell efferocytosis and cross-presentation in vivo.\",\n      \"evidence\": \"Co-IP with domain deletion, HDAC6 deacetylase assays, shRNA rescue of aggresome formation; in vivo DC-specific deletions, efferocytosis and cross-presentation assays, HSV-1 model\",\n      \"pmids\": [\"24795145\", \"24509082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC6 inhibition requires intact CTLH E3 activity not fully resolved here\", \"Direct vs indirect bridging of AXL-LRP-1 mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped RANBP9 nucleocytoplasmic shuttling determinants and showed CTLH-complex-mediated HDAC6 inhibition restrains migration, plus the SSH1-cofilin axis underlying its neurotoxic activity in vivo.\",\n      \"evidence\": \"Systematic NLS/NES deletion analysis with fractionation; Co-IP of CTLH members with HDAC6 and migration assays; SSH1-dependent cofilin translocation and APP/PS1 mouse rescue with LTP and behavior\",\n      \"pmids\": [\"25659156\", \"28668087\", \"25741591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DNA damage triggers the NES-dependent shift not defined\", \"Whether SSH1 regulation is direct or via the CTLH complex unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Solved the SPRY domain structure to define its peptide-binding surface, and established RANBP9 as an ATM substrate that promotes the DNA damage response and supports c-Kit protein stability.\",\n      \"evidence\": \"X-ray crystallography of apo and DDX4-peptide complex with mutagenesis; ATM phospho-site mapping (S181/S603), nuclear accumulation with ATM inhibition, HR reporter; Co-IP and null-mouse c-Kit protein/mRNA analysis\",\n      \"pmids\": [\"27622290\", \"26943034\", \"27835883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATM phosphorylation drives nuclear accumulation mechanistically incomplete\", \"Whether SPRY surface mediates all kinase interactions not generalized structurally\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the molecular basis of RANBP9's DDR function by showing it stabilizes p21 through USP11 recruitment in a p53-independent manner.\",\n      \"evidence\": \"Co-IP of RanBP9-p21-USP11, in vivo ubiquitylation assay, overexpression/silencing, and ATM-dependent nuclear translocation with DDR readouts\",\n      \"pmids\": [\"37676377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p21 stabilization involves the CTLH complex not addressed\", \"Single-lab finding without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed tissue- and tag-specific RANBP9 interactomes and paralog interplay, showing RANBP9 and RANBP10 independently nucleate the CTLH complex and antagonistically tune its ubiquitylation output.\",\n      \"evidence\": \"In vivo TurnX knock-in macrophage proteomics with tag-switching control; inducible NSCLC overexpression/loss-of-function with proteomics and ubiquitylome profiling and patient lysates\",\n      \"pmids\": [\"40223093\", \"40883813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates uniquely specified by RANBP9 vs RANBP10 not fully defined\", \"Functional consequences of macrophage-specific interactions not validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct substrate repertoire of the RANBP9-containing CTLH E3 ligase and how RANBP9's scaffolding choices are selected across tissues and signaling states remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined catalytic ubiquitination substrate set attributable specifically to RANBP9\", \"Rules governing partner selection among receptors, DDR factors, and apoptotic effectors unknown\", \"Structural basis for assembly into the full CTLH complex not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 26, 44, 52]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [19, 56]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [43, 46, 4]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [51]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 47, 49]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 9, 47]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [47, 46]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [47]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [49, 54]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [28, 39, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 31, 38]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 19, 56]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [44]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [26, 45, 48]}\n    ],\n    \"complexes\": [\"CTLH complex\"],\n    \"partners\": [\"MUSKELIN\", \"USP11\", \"HDAC6\", \"AXL\", \"LRP1\", \"MET\", \"COPS5\", \"CDKN1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}