{"gene":"RAI14","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2000,"finding":"NORPEG (RAI14) encodes a ~110 kDa protein with six ankyrin repeats and a long coiled-coil domain; when transiently expressed in COS-7 cells as a FLAG fusion, it localizes to the cytoplasm in thread-like projections reminiscent of the cytoskeleton, and the expressed protein shows resistance to solubilization by Triton X-100 and KCl, consistent with cytoskeletal association.","method":"Transient expression of FLAG-fusion protein in COS-7 cells, confocal immunofluorescence, detergent fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with biochemical fractionation, single lab, two orthogonal methods","pmids":["11042181"],"is_preprint":false},{"year":2006,"finding":"NORPEG (RAI14) subcellular localization is cell-density dependent: it is predominantly nuclear in non-confluent ARPE-19 cells but shifts to cytoplasmic/cytoskeletal localization in confluent cultures. A conserved monopartite nuclear localization signal (PKKRKAP, residues 270–276) was identified; deletion and mutation analysis showed this NLS is indispensable for nuclear targeting.","method":"Confocal immunofluorescence with polyclonal antibody, GFP-fusion protein expression, deletion and point mutation analysis, expression in ARPE-19 and COS-7 cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiments combined with mutagenesis validating NLS function, single lab but multiple orthogonal methods","pmids":["16729964"],"is_preprint":false},{"year":2013,"finding":"RAI14 is an actin-binding protein expressed at the ectoplasmic specialization (ES) in rat testis; it co-associates with the actin cross-linking protein palladin. RNAi knockdown of Rai14 in Sertoli cells in vitro disrupted F-actin organization and perturbed tight junction-permeability barrier function; in vivo knockdown caused defects in spermatid polarity, adhesion, and transport via changes in F-actin organization and protein mis-localization at the apical ES.","method":"RNAi knockdown in vitro and in vivo, co-immunoprecipitation/binding assays with actin and palladin, immunofluorescence, tight junction permeability assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding demonstrated, functional RNAi in two systems (in vitro and in vivo) with defined phenotypic readouts, single lab but multiple orthogonal methods","pmids":["23565266"],"is_preprint":false},{"year":2013,"finding":"RAI14 binds directly to both F-actin and palladin (an actin cross-linking/bundling protein) in the testis, functioning as a regulator of actin filament bundle integrity at the ectoplasmic specialization during spermatogenesis.","method":"Co-immunoprecipitation, immunofluorescence co-localization, functional RNAi studies","journal":"Spermatogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP binding data replicated across two publications from same lab, with functional follow-up","pmids":["23885305"],"is_preprint":false},{"year":2018,"finding":"RAI14 knockdown in gastric cancer cells inhibited proliferation, migration, and invasion, and promoted apoptosis by downregulating Bcl-2 and upregulating Bax; the mechanism was linked to inhibition of Akt pathway activation, and overexpression of RAB31 rescued the reduced proliferation caused by RAI14 knockdown, placing RAB31 downstream of RAI14.","method":"siRNA knockdown, cell proliferation/migration/invasion assays, flow cytometry apoptosis, Western blot, Akt pathway activation with IGF-1, RAB31 rescue experiments","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway placement and rescue experiment, single lab, multiple assays","pmids":["30349303"],"is_preprint":false},{"year":2018,"finding":"RAI14 promotes mTOR-mediated NF-κB inflammatory signaling in U87 glioblastoma cells; RAI14 knockdown attenuated pro-inflammatory cytokine production via inhibition of the IKK/NF-κB pathway, and mTOR inhibitor (everolimus) reduced NF-κB activity and IKKα/β phosphorylation through RAI14 signaling. RAI14 also enhanced mTOR-mediated NF-κB activation under chemical hypoxia.","method":"siRNA knockdown, mTOR inhibitor (everolimus) treatment, Western blot for IKK/NF-κB pathway components, LPS/TNF-α and CoCl2 stimulation models","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with pathway placement via inhibitor, single lab, single model system","pmids":["30554401"],"is_preprint":false},{"year":2019,"finding":"RAI14 knockdown in breast cancer cells inhibits proliferation, migration, and invasion by regulating cell cycle and EMT through the Akt/Cyclin D1 axis and modulating MMP2, MMP9, and ZEB1/E-cadherin/Vimentin pathway.","method":"siRNA knockdown, cell proliferation/migration/invasion assays, Western blot for pathway markers","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with Western blot pathway markers, no rescue or reconstitution","pmids":["31772666"],"is_preprint":false},{"year":2020,"finding":"RAI14 silencing in esophageal cancer cells induces apoptosis and cell cycle arrest; RAI14 activates the STAT3 pathway, upregulates Mcl-1 and cyclin D1, and inhibits cleaved caspase-3; STAT3 inhibition restored the oncogenic effect of RAI14.","method":"siRNA knockdown, overexpression, Western blot, STAT3 inhibitor rescue, in vivo xenograft","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with pathway inhibitor rescue, in vitro and in vivo, single lab","pmids":["32957082"],"is_preprint":false},{"year":2021,"finding":"Rai14 knockout (via CRISPR/Cas9) in mice did not disrupt spermatogenesis, fertility, sperm parameters, F-actin organization at the ectoplasmic specialization, or ES junction morphology — in contrast to results from siRNA knockdown in rats. This negative result indicates Rai14 is dispensable for mouse spermatogenesis.","method":"CRISPR/Cas9 knockout, CASA sperm analysis, histology, immunofluorescence, TEM, TUNEL assay","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous genetic KO with multiple phenotypic readouts; reported as negative finding, contradicting prior RNAi data","pmids":["33643708"],"is_preprint":false},{"year":2022,"finding":"The deubiquitinase STAMBP physically interacts with RAI14 and stabilizes it by suppressing K48-linked ubiquitination of RAI14, preventing its proteasomal degradation; STAMBP knockdown reduces RAI14 protein levels and suppresses TNBC tumor growth in vitro and in vivo.","method":"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, siRNA knockdown, ubiquitination assays (K48-linked), in vitro and in vivo tumor growth assays","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — IP-MS identification of interaction confirmed by Co-IP, mechanistic ubiquitination assay demonstrating K48-linked modification, functional rescue in vitro and in vivo, single lab with multiple orthogonal methods","pmids":["36434041"],"is_preprint":false},{"year":2022,"finding":"RAI14 affects the transcriptional expression of FBXO32 (an E3 ubiquitin ligase for c-MYC) and thereby regulates the stability of c-MYC protein in melanoma cells; RAI14 expression affects proliferation and invasion of melanoma cells.","method":"RAI14 overexpression/knockdown, Western blot for FBXO32 and c-MYC, cell proliferation and invasion assays","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic link between RAI14 and FBXO32/c-MYC inferred from expression changes without direct binding or biochemical reconstitution","pmids":["36233342"],"is_preprint":false},{"year":2023,"finding":"RAI14 interacts with Invariant chain (Ii/CD74) as identified by yeast two-hybrid screening, confirmed by co-immunoprecipitation; RAI14 localizes to membrane ruffles and macropinosomes. Depletion of RAI14 in antigen-presenting cells delays MHC II internalization and reduces macropinocytic activity. RAI14 also binds myosin II, suggesting RAI14, Ii, and myosin II cooperate to coordinate macropinocytosis and cell motility.","method":"Yeast two-hybrid screening, co-immunoprecipitation, immunofluorescence localization, RAI14 depletion with functional macropinocytosis and MHC II internalization assays, myosin II binding assay","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, direct localization experiments, depletion with defined functional readouts (macropinocytosis, MHC II trafficking), myosin II binding, multiple orthogonal methods in single study","pmids":["37545539"],"is_preprint":false},{"year":2025,"finding":"RA-induced RAI14 upregulation in renal fibroblasts promotes fibroblast-to-myofibroblast transition; RAI14 binds and stabilizes TRIOBP by preventing HECTD1-mediated ubiquitination and degradation of TRIOBP. This stabilization enhances F-actin assembly and cytoskeletal tension, leading to YAP nuclear translocation and activation of profibrotic transcriptional programs. Genetic ablation of RAI14 significantly attenuates renal fibrosis in vivo.","method":"Spatial metabolomics, single-cell transcriptomics, co-immunoprecipitation (RAI14-TRIOBP interaction), ubiquitination assays (HECTD1-mediated), F-actin assembly assays, YAP nuclear translocation assays, RAI14 genetic knockout in vivo fibrosis model","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical interaction and ubiquitination mechanism established, functional in vivo KO with defined fibrosis phenotype, multiple orthogonal methods in single study","pmids":["41242366"],"is_preprint":false},{"year":2025,"finding":"RNASEH2C enhances TRAF3IP1 expression to promote lysosomal degradation of RAI14, suppressing the mTOR pathway; HSC70 and CMTM6 play opposing roles in RAI14 degradation. RAI14 functions as a skeletal protein that facilitates macropinocytosis of MHC II molecules and tumor-associated antigen in macrophages, thereby activating Th1 cells in hepatocellular carcinoma.","method":"Single-cell RNA sequencing, immunoblotting, immunofluorescence, immunoprecipitation, flow cytometry, in vitro and mouse tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation for interactions, functional depletion with defined immune readouts, single lab","pmids":["41361104"],"is_preprint":false},{"year":2025,"finding":"RAI14, EPHA2, and PHACTR4 are components of the Wnt/PCP pathway identified by BioID proximity interactomics with key PCP components (ROR1, ROR2, VANGL2, DVL3, PRICKLE1); loss-of-function of rai14 in zebrafish disrupted convergent extension, orientation of lateral organ cells, and migration of melanoma cells (Wnt/PCP-dependent processes). Mechanistically, RAI14 connects the receptor complex to effector actomyosin.","method":"BioID proximity-dependent biotinylation interactomics, zebrafish loss-of-function (convergent extension, lateral organ orientation, melanoma cell migration assays)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID interactomics plus in vivo zebrafish loss-of-function with multiple Wnt/PCP phenotypic readouts; preprint, not yet peer reviewed","pmids":["bio_10.1101_2025.01.15.633117"],"is_preprint":true}],"current_model":"RAI14 is an actin-binding cytoskeletal adaptor protein containing ankyrin repeats and a coiled-coil domain that regulates F-actin dynamics and cytoskeletal organization; it binds palladin, myosin II, TRIOBP, and Invariant chain (CD74), participates in Wnt/PCP signaling by linking receptor complexes to actomyosin, facilitates macropinocytosis and MHC II trafficking in antigen-presenting cells, promotes fibroblast-to-myofibroblast transition via a RA-RAI14-TRIOBP-YAP mechanotransduction axis, and is stabilized post-translationally by the deubiquitinase STAMBP through suppression of K48-linked proteasomal ubiquitination; its subcellular localization is cell-density dependent, shifting between nuclear (via a defined NLS) and cytoplasmic/cytoskeletal compartments."},"narrative":{"mechanistic_narrative":"RAI14 (NORPEG) is an actin-binding cytoskeletal adaptor protein with six ankyrin repeats and a long coiled-coil domain that organizes F-actin and couples receptor and signaling complexes to the actomyosin network [PMID:11042181, PMID:23565266]. Its localization is cell-density dependent, partitioning between the nucleus—via a defined monopartite NLS (PKKRKAP, residues 270–276)—in sparse cells and cytoplasmic/cytoskeletal compartments in confluent cells [PMID:16729964]. At the testicular ectoplasmic specialization it binds directly to F-actin and the actin cross-linker palladin to maintain actin filament bundle integrity, adhesion, and the permeability barrier [PMID:23565266, PMID:23885305], although CRISPR knockout demonstrated RAI14 is dispensable for mouse spermatogenesis [PMID:33643708]. RAI14 acts as a cytoskeletal effector in distinct contexts: it interacts with Invariant chain (CD74) and myosin II at membrane ruffles and macropinosomes to drive macropinocytosis and MHC II trafficking in antigen-presenting cells [PMID:37545539], and proximity interactomics place it in the Wnt/PCP pathway alongside ROR1/2, VANGL2, DVL3 and PRICKLE1, where it links the receptor complex to effector actomyosin to control convergent extension and cell orientation [PMID:bio_10.1101_2025.01.15.633117]. In renal fibrosis, RAI14 binds and stabilizes TRIOBP by blocking HECTD1-mediated ubiquitination, enhancing F-actin assembly and cytoskeletal tension that drive YAP nuclear translocation and profibrotic transcription [PMID:41242366]. RAI14 protein abundance is set post-translationally: the deubiquitinase STAMBP stabilizes it by suppressing K48-linked ubiquitination and proteasomal degradation [PMID:36434041]. Across multiple cancers, RAI14 promotes proliferation, migration, and invasion through pathways including Akt and STAT3 signaling [PMID:30349303, PMID:32957082].","teleology":[{"year":2000,"claim":"Established RAI14 as a cytoskeleton-associated protein, defining its core architecture before any binding partner or pathway was known.","evidence":"FLAG-fusion expression in COS-7 cells with confocal imaging and detergent fractionation","pmids":["11042181"],"confidence":"Medium","gaps":["No direct actin binding demonstrated","No physiological partner identified","Cytoskeletal association inferred from solubility, not direct interaction"]},{"year":2006,"claim":"Resolved that RAI14 localization is regulated, identifying a functional NLS and a nuclear-cytoplasmic shift tied to cell density.","evidence":"GFP-fusion expression with NLS deletion/point mutagenesis in ARPE-19 and COS-7 cells","pmids":["16729964"],"confidence":"High","gaps":["Nuclear function of RAI14 unresolved","Signal coupling density to localization unknown","No nuclear binding partners identified"]},{"year":2013,"claim":"Defined RAI14's molecular activity as a direct F-actin and palladin binder that maintains actin bundle integrity at the ectoplasmic specialization.","evidence":"Reciprocal Co-IP/binding assays and RNAi knockdown in rat Sertoli cells in vitro and in vivo","pmids":["23565266","23885305"],"confidence":"High","gaps":["Binding interface mapping not done","Mechanism of actin bundle regulation unresolved","RNAi-only loss of function"]},{"year":2021,"claim":"Tested the genetic requirement for RAI14 in spermatogenesis, revealing it is dispensable in mouse and contradicting the rat RNAi phenotype.","evidence":"CRISPR/Cas9 knockout mice with CASA, histology, TEM, immunofluorescence, TUNEL","pmids":["33643708"],"confidence":"Medium","gaps":["Source of species discrepancy unexplained","Possible genetic compensation untested","Does not address non-testis roles"]},{"year":2022,"claim":"Identified the post-translational mechanism setting RAI14 abundance, linking STAMBP deubiquitinase activity to RAI14 stability.","evidence":"IP-MS, Co-IP, K48-linked ubiquitination assays, and TNBC tumor growth assays in vitro and in vivo","pmids":["36434041"],"confidence":"High","gaps":["E3 ligase opposing STAMBP not identified here","Ubiquitination sites on RAI14 unmapped","Functional consequence of stabilized RAI14 in cytoskeleton not addressed"]},{"year":2023,"claim":"Placed RAI14 in membrane trafficking, showing it bridges Invariant chain and myosin II to drive macropinocytosis and MHC II internalization.","evidence":"Yeast two-hybrid, Co-IP, immunofluorescence, and depletion with macropinocytosis/MHC II internalization functional assays in antigen-presenting cells","pmids":["37545539"],"confidence":"High","gaps":["Stoichiometry of RAI14-Ii-myosin II complex unknown","Whether macropinocytosis role is direct or via actin remodeling unresolved","In vivo immune relevance not established here"]},{"year":2025,"claim":"Defined a mechanotransduction axis in which RAI14 stabilizes TRIOBP against HECTD1 ubiquitination to drive actin tension and YAP-mediated profibrotic transcription.","evidence":"Spatial metabolomics, single-cell transcriptomics, Co-IP, ubiquitination assays, F-actin/YAP translocation assays, and RAI14 knockout in an in vivo renal fibrosis model","pmids":["41242366"],"confidence":"High","gaps":["Direct RAI14-TRIOBP binding interface unmapped","How RAI14 blocks HECTD1 access mechanistically unclear","Generality beyond renal fibroblasts untested"]},{"year":2025,"claim":"Extended RAI14 into Wnt/PCP signaling, positioning it as a connector between PCP receptor complexes and effector actomyosin.","evidence":"BioID proximity interactomics with PCP components and zebrafish loss-of-function (convergent extension, lateral organ orientation, melanoma migration) (preprint)","pmids":["bio_10.1101_2025.01.15.633117"],"confidence":"Medium","gaps":["Proximity labeling does not prove direct binding","Preprint, not peer reviewed","Direct receptor-RAI14 contact not demonstrated"]},{"year":null,"claim":"How RAI14's regulated nuclear-cytoplasmic shuttling, its actin-organizing activity, and its multiple signaling roles (Wnt/PCP, mTOR, YAP, trafficking) are integrated into a single coherent function remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of RAI14 bound to actin or partners","Nuclear role of RAI14 entirely uncharacterized","Unified mechanism reconciling cancer, fibrosis, immune, and developmental roles absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,12,14]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,13]}],"complexes":[],"partners":["PALLD","ACTB","CD74","MYH9","STAMBP","TRIOBP","VANGL2","DVL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0K7","full_name":"Ankycorbin","aliases":["Ankyrin repeat and coiled-coil structure-containing protein","Novel retinal pigment epithelial cell protein","Retinoic acid-induced protein 14"],"length_aa":980,"mass_kda":110.0,"function":"Plays a role in actin regulation at the ectoplasmic specialization, a type of cell junction specific to testis. Important for establishment of sperm polarity and normal spermatid adhesion. May also promote integrity of Sertoli cell tight junctions at the blood-testis barrier","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, stress fiber; Cytoplasm, cell cortex; Cell junction; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P0K7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAI14","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"PACSIN2","stoichiometry":0.2},{"gene":"PACSIN3","stoichiometry":0.2},{"gene":"PSMD9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAI14","total_profiled":1310},"omim":[{"mim_id":"606586","title":"RETINOIC ACID-INDUCED 14; RAI14","url":"https://www.omim.org/entry/606586"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAI14"},"hgnc":{"alias_symbol":["NORPEG","KIAA1334","RAI13","DKFZp564G013"],"prev_symbol":[]},"alphafold":{"accession":"Q9P0K7","domains":[{"cath_id":"1.25.40.20","chopping":"17-246","consensus_level":"medium","plddt":87.4115,"start":17,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0K7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0K7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0K7-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAI14","jax_strain_url":"https://www.jax.org/strain/search?query=RAI14"},"sequence":{"accession":"Q9P0K7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0K7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0K7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0K7"}},"corpus_meta":[{"pmid":"11042181","id":"PMC_11042181","title":"Molecular characterization and developmental expression of NORPEG, a novel gene induced by retinoic acid.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11042181","citation_count":44,"is_preprint":false},{"pmid":"32228518","id":"PMC_32228518","title":"Long non-coding RNA AFAP1-AS1 accelerates the progression of melanoma by targeting miR-653-5p/RAI14 axis.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32228518","citation_count":40,"is_preprint":false},{"pmid":"33643708","id":"PMC_33643708","title":"Retinoic Acid Induced Protein 14 (Rai14) is dispensable for mouse spermatogenesis.","date":"2021","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/33643708","citation_count":30,"is_preprint":false},{"pmid":"36434041","id":"PMC_36434041","title":"The deubiquitinating enzyme STAMBP is a newly discovered driver of triple-negative breast cancer progression that maintains RAI14 protein stability.","date":"2022","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36434041","citation_count":28,"is_preprint":false},{"pmid":"23565266","id":"PMC_23565266","title":"Rai14 (retinoic acid induced protein 14) is involved in regulating f-actin dynamics at the ectoplasmic specialization in the rat testis*.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23565266","citation_count":24,"is_preprint":false},{"pmid":"30349303","id":"PMC_30349303","title":"Knockdown of RAI14 suppresses the progression of gastric cancer.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30349303","citation_count":21,"is_preprint":false},{"pmid":"30554401","id":"PMC_30554401","title":"Retinoic Acid-Induced Protein 14 (RAI14) Promotes mTOR-Mediated Inflammation Under Inflammatory Stress and Chemical Hypoxia in a U87 Glioblastoma Cell Line.","date":"2018","source":"Cellular and molecular 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novel alternative transcript of the novel retinal pigment epithelial cell gene NORPEG in human testes.","date":"2005","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/16110356","citation_count":17,"is_preprint":false},{"pmid":"23885305","id":"PMC_23885305","title":"RAI14 (retinoic acid induced protein 14) is an F-actin regulator: Lesson from the testis.","date":"2013","source":"Spermatogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23885305","citation_count":15,"is_preprint":false},{"pmid":"34275467","id":"PMC_34275467","title":"Bta-miR-34b controls milk fat biosynthesis via the Akt/mTOR signaling pathway by targeting RAI14 in bovine mammary epithelial cells.","date":"2021","source":"Journal of animal science and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34275467","citation_count":14,"is_preprint":false},{"pmid":"33840258","id":"PMC_33840258","title":"RAI14 Regulated by circNFATC3/miR-23b-3p axis Facilitates Cell Growth and Invasion in Gastric 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diagnosis and chemosurveillance in triple negative breast cancer.","date":"2023","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36880986","citation_count":3,"is_preprint":false},{"pmid":"41361104","id":"PMC_41361104","title":"RNASEH2C enhances TRAF3IP1 to degrade RAI14 in lysosomes thus hindering macrophage antigen presentation and advancing liver cancer.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41361104","citation_count":1,"is_preprint":false},{"pmid":"40902302","id":"PMC_40902302","title":"Unveiling the role of RAI14 in cancer: Biological significance and translational perspectives.","date":"2025","source":"Seminars in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40902302","citation_count":0,"is_preprint":false},{"pmid":"41242366","id":"PMC_41242366","title":"Renal tubular-derived retinoic acid drives renal fibrosis via a RAI14-TRIOBP-YAP mechanotransduction axis.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41242366","citation_count":0,"is_preprint":false},{"pmid":"41540697","id":"PMC_41540697","title":"[Antitumor component-Ι in Agkistrodon halys venom inhibits proliferation and migration of cisplatin-resistant gastric cancer cells by downregulating RAI14].","date":"2026","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/41540697","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.15.633117","title":"Proximity interactomics identifies RAI14, EPHA2 and PHACTR4 as essential components of Wnt/planar cell polarity pathway in vertebrates","date":"2025-01-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.15.633117","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14720,"output_tokens":4110,"usd":0.052905,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11960,"output_tokens":3185,"usd":0.069712,"stage2_stop_reason":"end_turn"},"total_usd":0.122617,"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\": 2000,\n      \"finding\": \"NORPEG (RAI14) encodes a ~110 kDa protein with six ankyrin repeats and a long coiled-coil domain; when transiently expressed in COS-7 cells as a FLAG fusion, it localizes to the cytoplasm in thread-like projections reminiscent of the cytoskeleton, and the expressed protein shows resistance to solubilization by Triton X-100 and KCl, consistent with cytoskeletal association.\",\n      \"method\": \"Transient expression of FLAG-fusion protein in COS-7 cells, confocal immunofluorescence, detergent fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with biochemical fractionation, single lab, two orthogonal methods\",\n      \"pmids\": [\"11042181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NORPEG (RAI14) subcellular localization is cell-density dependent: it is predominantly nuclear in non-confluent ARPE-19 cells but shifts to cytoplasmic/cytoskeletal localization in confluent cultures. A conserved monopartite nuclear localization signal (PKKRKAP, residues 270–276) was identified; deletion and mutation analysis showed this NLS is indispensable for nuclear targeting.\",\n      \"method\": \"Confocal immunofluorescence with polyclonal antibody, GFP-fusion protein expression, deletion and point mutation analysis, expression in ARPE-19 and COS-7 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments combined with mutagenesis validating NLS function, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16729964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAI14 is an actin-binding protein expressed at the ectoplasmic specialization (ES) in rat testis; it co-associates with the actin cross-linking protein palladin. RNAi knockdown of Rai14 in Sertoli cells in vitro disrupted F-actin organization and perturbed tight junction-permeability barrier function; in vivo knockdown caused defects in spermatid polarity, adhesion, and transport via changes in F-actin organization and protein mis-localization at the apical ES.\",\n      \"method\": \"RNAi knockdown in vitro and in vivo, co-immunoprecipitation/binding assays with actin and palladin, immunofluorescence, tight junction permeability assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding demonstrated, functional RNAi in two systems (in vitro and in vivo) with defined phenotypic readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23565266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAI14 binds directly to both F-actin and palladin (an actin cross-linking/bundling protein) in the testis, functioning as a regulator of actin filament bundle integrity at the ectoplasmic specialization during spermatogenesis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, functional RNAi studies\",\n      \"journal\": \"Spermatogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP binding data replicated across two publications from same lab, with functional follow-up\",\n      \"pmids\": [\"23885305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAI14 knockdown in gastric cancer cells inhibited proliferation, migration, and invasion, and promoted apoptosis by downregulating Bcl-2 and upregulating Bax; the mechanism was linked to inhibition of Akt pathway activation, and overexpression of RAB31 rescued the reduced proliferation caused by RAI14 knockdown, placing RAB31 downstream of RAI14.\",\n      \"method\": \"siRNA knockdown, cell proliferation/migration/invasion assays, flow cytometry apoptosis, Western blot, Akt pathway activation with IGF-1, RAB31 rescue experiments\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway placement and rescue experiment, single lab, multiple assays\",\n      \"pmids\": [\"30349303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAI14 promotes mTOR-mediated NF-κB inflammatory signaling in U87 glioblastoma cells; RAI14 knockdown attenuated pro-inflammatory cytokine production via inhibition of the IKK/NF-κB pathway, and mTOR inhibitor (everolimus) reduced NF-κB activity and IKKα/β phosphorylation through RAI14 signaling. RAI14 also enhanced mTOR-mediated NF-κB activation under chemical hypoxia.\",\n      \"method\": \"siRNA knockdown, mTOR inhibitor (everolimus) treatment, Western blot for IKK/NF-κB pathway components, LPS/TNF-α and CoCl2 stimulation models\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with pathway placement via inhibitor, single lab, single model system\",\n      \"pmids\": [\"30554401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAI14 knockdown in breast cancer cells inhibits proliferation, migration, and invasion by regulating cell cycle and EMT through the Akt/Cyclin D1 axis and modulating MMP2, MMP9, and ZEB1/E-cadherin/Vimentin pathway.\",\n      \"method\": \"siRNA knockdown, cell proliferation/migration/invasion assays, Western blot for pathway markers\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with Western blot pathway markers, no rescue or reconstitution\",\n      \"pmids\": [\"31772666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAI14 silencing in esophageal cancer cells induces apoptosis and cell cycle arrest; RAI14 activates the STAT3 pathway, upregulates Mcl-1 and cyclin D1, and inhibits cleaved caspase-3; STAT3 inhibition restored the oncogenic effect of RAI14.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot, STAT3 inhibitor rescue, in vivo xenograft\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with pathway inhibitor rescue, in vitro and in vivo, single lab\",\n      \"pmids\": [\"32957082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rai14 knockout (via CRISPR/Cas9) in mice did not disrupt spermatogenesis, fertility, sperm parameters, F-actin organization at the ectoplasmic specialization, or ES junction morphology — in contrast to results from siRNA knockdown in rats. This negative result indicates Rai14 is dispensable for mouse spermatogenesis.\",\n      \"method\": \"CRISPR/Cas9 knockout, CASA sperm analysis, histology, immunofluorescence, TEM, TUNEL assay\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous genetic KO with multiple phenotypic readouts; reported as negative finding, contradicting prior RNAi data\",\n      \"pmids\": [\"33643708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The deubiquitinase STAMBP physically interacts with RAI14 and stabilizes it by suppressing K48-linked ubiquitination of RAI14, preventing its proteasomal degradation; STAMBP knockdown reduces RAI14 protein levels and suppresses TNBC tumor growth in vitro and in vivo.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, siRNA knockdown, ubiquitination assays (K48-linked), in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — IP-MS identification of interaction confirmed by Co-IP, mechanistic ubiquitination assay demonstrating K48-linked modification, functional rescue in vitro and in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36434041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RAI14 affects the transcriptional expression of FBXO32 (an E3 ubiquitin ligase for c-MYC) and thereby regulates the stability of c-MYC protein in melanoma cells; RAI14 expression affects proliferation and invasion of melanoma cells.\",\n      \"method\": \"RAI14 overexpression/knockdown, Western blot for FBXO32 and c-MYC, cell proliferation and invasion assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic link between RAI14 and FBXO32/c-MYC inferred from expression changes without direct binding or biochemical reconstitution\",\n      \"pmids\": [\"36233342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAI14 interacts with Invariant chain (Ii/CD74) as identified by yeast two-hybrid screening, confirmed by co-immunoprecipitation; RAI14 localizes to membrane ruffles and macropinosomes. Depletion of RAI14 in antigen-presenting cells delays MHC II internalization and reduces macropinocytic activity. RAI14 also binds myosin II, suggesting RAI14, Ii, and myosin II cooperate to coordinate macropinocytosis and cell motility.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, immunofluorescence localization, RAI14 depletion with functional macropinocytosis and MHC II internalization assays, myosin II binding assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, direct localization experiments, depletion with defined functional readouts (macropinocytosis, MHC II trafficking), myosin II binding, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37545539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RA-induced RAI14 upregulation in renal fibroblasts promotes fibroblast-to-myofibroblast transition; RAI14 binds and stabilizes TRIOBP by preventing HECTD1-mediated ubiquitination and degradation of TRIOBP. This stabilization enhances F-actin assembly and cytoskeletal tension, leading to YAP nuclear translocation and activation of profibrotic transcriptional programs. Genetic ablation of RAI14 significantly attenuates renal fibrosis in vivo.\",\n      \"method\": \"Spatial metabolomics, single-cell transcriptomics, co-immunoprecipitation (RAI14-TRIOBP interaction), ubiquitination assays (HECTD1-mediated), F-actin assembly assays, YAP nuclear translocation assays, RAI14 genetic knockout in vivo fibrosis model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical interaction and ubiquitination mechanism established, functional in vivo KO with defined fibrosis phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41242366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNASEH2C enhances TRAF3IP1 expression to promote lysosomal degradation of RAI14, suppressing the mTOR pathway; HSC70 and CMTM6 play opposing roles in RAI14 degradation. RAI14 functions as a skeletal protein that facilitates macropinocytosis of MHC II molecules and tumor-associated antigen in macrophages, thereby activating Th1 cells in hepatocellular carcinoma.\",\n      \"method\": \"Single-cell RNA sequencing, immunoblotting, immunofluorescence, immunoprecipitation, flow cytometry, in vitro and mouse tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation for interactions, functional depletion with defined immune readouts, single lab\",\n      \"pmids\": [\"41361104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAI14, EPHA2, and PHACTR4 are components of the Wnt/PCP pathway identified by BioID proximity interactomics with key PCP components (ROR1, ROR2, VANGL2, DVL3, PRICKLE1); loss-of-function of rai14 in zebrafish disrupted convergent extension, orientation of lateral organ cells, and migration of melanoma cells (Wnt/PCP-dependent processes). Mechanistically, RAI14 connects the receptor complex to effector actomyosin.\",\n      \"method\": \"BioID proximity-dependent biotinylation interactomics, zebrafish loss-of-function (convergent extension, lateral organ orientation, melanoma cell migration assays)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID interactomics plus in vivo zebrafish loss-of-function with multiple Wnt/PCP phenotypic readouts; preprint, not yet peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.15.633117\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RAI14 is an actin-binding cytoskeletal adaptor protein containing ankyrin repeats and a coiled-coil domain that regulates F-actin dynamics and cytoskeletal organization; it binds palladin, myosin II, TRIOBP, and Invariant chain (CD74), participates in Wnt/PCP signaling by linking receptor complexes to actomyosin, facilitates macropinocytosis and MHC II trafficking in antigen-presenting cells, promotes fibroblast-to-myofibroblast transition via a RA-RAI14-TRIOBP-YAP mechanotransduction axis, and is stabilized post-translationally by the deubiquitinase STAMBP through suppression of K48-linked proteasomal ubiquitination; its subcellular localization is cell-density dependent, shifting between nuclear (via a defined NLS) and cytoplasmic/cytoskeletal compartments.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAI14 (NORPEG) is an actin-binding cytoskeletal adaptor protein with six ankyrin repeats and a long coiled-coil domain that organizes F-actin and couples receptor and signaling complexes to the actomyosin network [#0, #2]. Its localization is cell-density dependent, partitioning between the nucleus—via a defined monopartite NLS (PKKRKAP, residues 270–276)—in sparse cells and cytoplasmic/cytoskeletal compartments in confluent cells [#1]. At the testicular ectoplasmic specialization it binds directly to F-actin and the actin cross-linker palladin to maintain actin filament bundle integrity, adhesion, and the permeability barrier [#2, #3], although CRISPR knockout demonstrated RAI14 is dispensable for mouse spermatogenesis [#8]. RAI14 acts as a cytoskeletal effector in distinct contexts: it interacts with Invariant chain (CD74) and myosin II at membrane ruffles and macropinosomes to drive macropinocytosis and MHC II trafficking in antigen-presenting cells [#11], and proximity interactomics place it in the Wnt/PCP pathway alongside ROR1/2, VANGL2, DVL3 and PRICKLE1, where it links the receptor complex to effector actomyosin to control convergent extension and cell orientation [#14]. In renal fibrosis, RAI14 binds and stabilizes TRIOBP by blocking HECTD1-mediated ubiquitination, enhancing F-actin assembly and cytoskeletal tension that drive YAP nuclear translocation and profibrotic transcription [#12]. RAI14 protein abundance is set post-translationally: the deubiquitinase STAMBP stabilizes it by suppressing K48-linked ubiquitination and proteasomal degradation [#9]. Across multiple cancers, RAI14 promotes proliferation, migration, and invasion through pathways including Akt and STAT3 signaling [#4, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established RAI14 as a cytoskeleton-associated protein, defining its core architecture before any binding partner or pathway was known.\",\n      \"evidence\": \"FLAG-fusion expression in COS-7 cells with confocal imaging and detergent fractionation\",\n      \"pmids\": [\"11042181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct actin binding demonstrated\", \"No physiological partner identified\", \"Cytoskeletal association inferred from solubility, not direct interaction\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved that RAI14 localization is regulated, identifying a functional NLS and a nuclear-cytoplasmic shift tied to cell density.\",\n      \"evidence\": \"GFP-fusion expression with NLS deletion/point mutagenesis in ARPE-19 and COS-7 cells\",\n      \"pmids\": [\"16729964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear function of RAI14 unresolved\", \"Signal coupling density to localization unknown\", \"No nuclear binding partners identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined RAI14's molecular activity as a direct F-actin and palladin binder that maintains actin bundle integrity at the ectoplasmic specialization.\",\n      \"evidence\": \"Reciprocal Co-IP/binding assays and RNAi knockdown in rat Sertoli cells in vitro and in vivo\",\n      \"pmids\": [\"23565266\", \"23885305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface mapping not done\", \"Mechanism of actin bundle regulation unresolved\", \"RNAi-only loss of function\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested the genetic requirement for RAI14 in spermatogenesis, revealing it is dispensable in mouse and contradicting the rat RNAi phenotype.\",\n      \"evidence\": \"CRISPR/Cas9 knockout mice with CASA, histology, TEM, immunofluorescence, TUNEL\",\n      \"pmids\": [\"33643708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of species discrepancy unexplained\", \"Possible genetic compensation untested\", \"Does not address non-testis roles\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the post-translational mechanism setting RAI14 abundance, linking STAMBP deubiquitinase activity to RAI14 stability.\",\n      \"evidence\": \"IP-MS, Co-IP, K48-linked ubiquitination assays, and TNBC tumor growth assays in vitro and in vivo\",\n      \"pmids\": [\"36434041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase opposing STAMBP not identified here\", \"Ubiquitination sites on RAI14 unmapped\", \"Functional consequence of stabilized RAI14 in cytoskeleton not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed RAI14 in membrane trafficking, showing it bridges Invariant chain and myosin II to drive macropinocytosis and MHC II internalization.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, immunofluorescence, and depletion with macropinocytosis/MHC II internalization functional assays in antigen-presenting cells\",\n      \"pmids\": [\"37545539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of RAI14-Ii-myosin II complex unknown\", \"Whether macropinocytosis role is direct or via actin remodeling unresolved\", \"In vivo immune relevance not established here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a mechanotransduction axis in which RAI14 stabilizes TRIOBP against HECTD1 ubiquitination to drive actin tension and YAP-mediated profibrotic transcription.\",\n      \"evidence\": \"Spatial metabolomics, single-cell transcriptomics, Co-IP, ubiquitination assays, F-actin/YAP translocation assays, and RAI14 knockout in an in vivo renal fibrosis model\",\n      \"pmids\": [\"41242366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RAI14-TRIOBP binding interface unmapped\", \"How RAI14 blocks HECTD1 access mechanistically unclear\", \"Generality beyond renal fibroblasts untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended RAI14 into Wnt/PCP signaling, positioning it as a connector between PCP receptor complexes and effector actomyosin.\",\n      \"evidence\": \"BioID proximity interactomics with PCP components and zebrafish loss-of-function (convergent extension, lateral organ orientation, melanoma migration) (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.15.633117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximity labeling does not prove direct binding\", \"Preprint, not peer reviewed\", \"Direct receptor-RAI14 contact not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RAI14's regulated nuclear-cytoplasmic shuttling, its actin-organizing activity, and its multiple signaling roles (Wnt/PCP, mTOR, YAP, trafficking) are integrated into a single coherent function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of RAI14 bound to actin or partners\", \"Nuclear role of RAI14 entirely uncharacterized\", \"Unified mechanism reconciling cancer, fibrosis, immune, and developmental roles absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 12, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PALLD\", \"ACTB\", \"CD74\", \"MYH9\", \"STAMBP\", \"TRIOBP\", \"VANGL2\", \"DVL3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}