{"gene":"RARRES1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"RARRES1 (TIG1) is a novel retinoic acid receptor (RARbeta/gamma)-responsive gene encoding a transmembrane protein with a small N-terminal intracellular region, a single membrane-spanning hydrophobic domain, and a large C-terminal extracellular region containing a glycosylation signal; its expression is upregulated by RAR-selective but not RXR-selective retinoids.","method":"Subtraction hybridization, Northern/Southern blot, RAR/RXR-selective retinoid treatment in skin raft cultures","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — original discovery with multiple orthogonal methods; foundational paper with 113 citations","pmids":["8601727"],"is_preprint":false},{"year":2002,"finding":"TIG1 overexpression in the highly malignant prostate cancer cell line PC-3M significantly decreased in vitro invasiveness and in vivo tumorigenicity, establishing a functional tumor suppressor role.","method":"cDNA transfection, in vitro Matrigel invasion assay, in vivo nude mouse tumor growth assay","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function with defined cellular phenotypes in vitro and in vivo; 88 citations","pmids":["11929948"],"is_preprint":false},{"year":2005,"finding":"The crystal structure of mouse latexin (the only known mammalian carboxypeptidase inhibitor and homolog of TIG1/RARRES1) was solved at 1.83 Å, revealing a cystatin fold architecture with pseudo-two-fold symmetry; modeling of TIG1 structure identified a putative membrane-binding surface, indicating RARRES1 is structurally related to carboxypeptidase inhibitors.","method":"X-ray crystallography (1.83 Å resolution), structural modeling","journal":"Structure","confidence":"Medium","confidence_rationale":"Tier 1 for latexin crystal structure; RARRES1 model is computational, reducing overall confidence","pmids":["15698574"],"is_preprint":false},{"year":2011,"finding":"RARRES1 is a transmembrane carboxypeptidase inhibitor that directly interacts with AGBL2 (a cytoplasmic carboxypeptidase); knockdown of RARRES1 increases detyrosinated alpha-tubulin levels, consistent with RARRES1 acting as the cognate inhibitor of AGBL2 to regulate the tubulin tyrosination cycle and microtubule dynamics.","method":"Co-immunoprecipitation, AGBL2/RARRES1 siRNA knockdown, Western blot for tyrosinated/detyrosinated alpha-tubulin","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional interaction established by Co-IP and two independent knockdown experiments with specific biochemical readout; 57 citations","pmids":["21303978"],"is_preprint":false},{"year":2010,"finding":"RARRES1 knockdown in prostatic epithelial cells downregulates PP2A, valosin-containing protein (VCP), and EB1, and upregulates DLG2 and Ankrd26, placing RARRES1 upstream of multiple signaling nodes involved in growth regulation, autophagy, and spindle dynamics.","method":"siRNA knockdown, 2D-DIGE proteomics, MALDI mass spectrometry, Western blot","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus Western blot validation, single lab","pmids":["20842219"],"is_preprint":false},{"year":2013,"finding":"TIG1/RARRES1 interacts with the receptor tyrosine kinase Axl, stabilizing Axl by inhibiting its proteasome-dependent degradation; TIG1 depletion reduces Axl expression, inactivates NF-κB, and downregulates MMP-9, thereby regulating invasion of inflammatory breast cancer cells.","method":"Co-immunoprecipitation (TIG1-Axl interaction), siRNA depletion, Western blot for Axl/NF-κB/MMP-9, in vitro invasion/migration assays, in vivo tumor growth","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus functional rescue and in vivo validation in a single study; 68 citations","pmids":["24014597"],"is_preprint":false},{"year":2013,"finding":"RARRES1 resides primarily in the endoplasmic reticulum (not the plasma membrane), whereas its homolog LXN is nuclear; siRNA suppression of RARRES1 enhances colony-forming ability and invasive capacity of primary prostate epithelial cultures, and all-trans retinoic acid induces RARRES1 expression coordinately with differentiation.","method":"Immunofluorescence subcellular localization, siRNA knockdown, colony-forming assay, Matrigel invasion assay, retinoic acid treatment","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence plus loss-of-function phenotype; single lab","pmids":["23588494"],"is_preprint":false},{"year":2012,"finding":"Epigenetic silencing of RARRES1 is mediated by hypermethylation specifically at a proximal promoter element, and CTCF binds to the unmethylated promoter to positively regulate RARRES1 transcription; CTCF knockdown suppresses RARRES1 expression.","method":"Bisulfite sequencing, methylation-specific PCR, chromatin immunoprecipitation (CTCF), CTCF siRNA knockdown, reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus functional knockdown with multiple orthogonal methods; single lab","pmids":["22615834"],"is_preprint":false},{"year":2019,"finding":"RARRES1 interaction with cytoplasmic carboxypeptidase CCP2 inhibits tubulin deglutamylation, which in turn regulates mitochondrial VDAC1 interactions, mitochondrial membrane potential, and AMPK activation; depletion of RARRES1 increases stem cell markers and anoikis resistance, effects reversed by CCP2 depletion or VDAC1 inhibition.","method":"Co-immunoprecipitation, siRNA knockdown (RARRES1, CCP2), VDAC1 inhibitor treatment, mitochondrial membrane potential assay, AMPK/energy balance assays, zebrafish metabolic phenotyping","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway placed by epistasis (CCP2/VDAC1 rescue), multiple orthogonal methods, in vivo zebrafish validation","pmids":["30899431"],"is_preprint":false},{"year":2020,"finding":"Soluble RARRES1, generated by proteolytic cleavage of its extracellular domain, is endocytosed by podocytes and interacts with and inhibits RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis; mutation of the cleavage site abolishes the apoptotic effect, and podocyte-specific RARRES1 overexpression in mice causes glomerular injury and albuminuria.","method":"Co-immunoprecipitation (sRARRES1-RIOK1), cleavage-site mutagenesis, podocyte endocytosis assay, apoptosis assay, podocyte-specific transgenic/knockout mice, transcriptomic analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP, mutagenesis, in vitro apoptosis assay, and in vivo mouse models with specific phenotype; 76 citations","pmids":["32634130"],"is_preprint":false},{"year":2018,"finding":"RARRES1 depletion in epithelial cells causes global increase in lipid synthesis via de novo lipogenesis (DNL) by rewiring glucose metabolism; the increase in fatty acid availability supports mitochondrial fatty acid oxidation during starvation; RARRES1 expression is regulated by PPAR signaling.","method":"Non-targeted LC-MS lipidomics, FASN inhibitor (C75) rescue experiment, metabolic flux analysis, siRNA knockdown in breast and prostate epithelial cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multi-method metabolomics with pharmacological rescue; single lab","pmids":["30557378"],"is_preprint":false},{"year":2017,"finding":"RARRES1 overexpression in prostate cancer cell lines represses MAPK activation, induces autophagy (increases beclin, ATG3, LC3B-II), elevates SIRT1, inhibits mTOR, increases catalase, and inhibits angiogenesis in endothelial cells.","method":"cDNA overexpression, Western blot (autophagy markers, SIRT1, mTOR pathway), endothelial tube formation assay","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 — overexpression with Western blot readouts, single lab, no epistatic rescue or mechanistic target identification","pmids":["28678839"],"is_preprint":false},{"year":2019,"finding":"TIG1/RARRES1 interacts with serine protease inhibitor SPINK2 in NT2/D1 testicular carcinoma cells; SPINK2 enhances TIG1-mediated suppression of uPA activity and EMT, while SPINK2 silencing alleviates TIG1-mediated cell migration and invasion suppression.","method":"Co-immunoprecipitation (TIG1-SPINK2), siRNA knockdown of SPINK2, uPA activity assay, EMT marker Western blot, migration and invasion assays","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional epistasis via SPINK2 knockdown rescue; single lab","pmids":["31886233"],"is_preprint":false},{"year":2024,"finding":"Matrix metalloproteinase 23 (MMP23) is the podocyte-specific metalloproteinase responsible for cleaving RARRES1 to generate soluble RARRES1 (sRARRES1); AAV9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo and prevented RARRES1-driven glomerular and tubular injury.","method":"scRNA-seq to identify MMP23 expression, AAV9-mediated MMP23 knockdown in vivo, RARRES1 cleavage-mutant overexpression, histological assessment of kidney injury","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic knockdown with specific mechanistic readout, cleavage mutant controls, multiple CKD models","pmids":["38697478"],"is_preprint":false},{"year":2024,"finding":"sRARRES1 (soluble RARRES1) directly taken up by proximal tubular epithelial cells binds KHDRBS1, recruits Src kinase, and induces STAT3 phosphorylation at Tyr705, upregulating pro-fibrotic factors; proximal-tubule-specific Rarres1 knockout reduces kidney fibrosis, and STAT3/Src inhibition reverses the fibrotic phenotype.","method":"Mass spectrometry, co-immunoprecipitation with truncation mutants (sRARRES1-KHDRBS1-Src-pSTAT3), proximal-tubule-specific knockout mice (UUO and folic acid models), RARRES1-overexpressing mice, pharmacological STAT3/Src inhibition","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 1-2 — MS identification, Co-IP with domain mapping, in vivo genetic KO and OE with multiple CKD models, pharmacological rescue","pmids":["41955023"],"is_preprint":false},{"year":2023,"finding":"TIG1/RARRES1 interacts with VAC14 and inhibits insulin-induced mTORC1-p70 S6K activation in melanoma cells; TIG1 had no additional inhibitory effect on mTOR signaling in the absence of VAC14, indicating TIG1 suppresses mTOR primarily through VAC14, affecting PI(3,5)P2 rather than PI(4,5)P2 signaling.","method":"Co-immunoprecipitation (TIG1-VAC14), VAC14 knockdown epistasis, Western blot for mTORC1/p70 S6K/pAKT, cell proliferation assay","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus genetic epistasis via VAC14 knockdown; single lab","pmids":["37247911"],"is_preprint":false},{"year":2022,"finding":"Loss of Rarres1 in mice promotes follicular lymphoma development and impairs B cell activation, maturation, and differentiation into plasma cells; Rarres1-/- embryonic fibroblasts recapitulate in vitro defects in tubulin glutamylation and cell metabolism, confirming RARRES1 as a bona fide in vivo tumor suppressor.","method":"Constitutive Rarres1 knockout mouse model, flow cytometry (B cell differentiation), tumor histopathology, tubulin glutamylation assay, metabolic assays in primary fibroblasts","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO mouse with specific tumor phenotype and mechanistic recapitulation in primary cells","pmids":["35541897"],"is_preprint":false},{"year":2022,"finding":"Tig1/Rarres1 acts as a cell-surface determinant of proximal positional identity during salamander limb regeneration; its overexpression causes proximal displacement of blastema cells and regeneration defects in distal elements, upregulates Prod1, and inhibits Hoxa13 and distal transcriptional networks.","method":"Single-cell RNA-seq, Tig1 overexpression and neutralization in salamander blastema, in situ hybridization for Prod1/Hoxa13, proximo-distal cell surface interaction assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with specific positional identity readout in salamander; ortholog functional context consistent with mammalian RARRES1","pmids":["35241664"],"is_preprint":false},{"year":2012,"finding":"RARRES1 protein is secreted (as a soluble form) by NF1-derived plexiform neurofibroma Schwann cells but not by normal Schwann cells; all-trans retinoic acid modulates RARRES1 secretion in a dose-dependent manner.","method":"Secretome proteomics (SDS-PAGE + LC-MS/MS), conditioned media analysis, retinoic acid dose-response","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics-based identification of secreted form with dose-dependent retinoic acid regulation; single lab","pmids":["22942771"],"is_preprint":false},{"year":2016,"finding":"RARRES1 expression in basal-like triple-negative breast cancer is maintained by promoter hypomethylation and is driven by ALDH1A3-generated retinoic acid acting as RAR ligand; RARRES1 functions as a tumor suppressor in TNBC as shown by cell proliferation and tumor growth assays.","method":"Illumina HumanMethylation450 arrays, chromatin immunoprecipitation, siRNA/overexpression, cell proliferation assay, in vivo tumor growth","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus methylation arrays and functional assays establishing ALDH1A3-RA-RARRES1 regulatory axis; single lab","pmids":["27286452"],"is_preprint":false},{"year":2024,"finding":"TIG1/RARRES1 induces trophoblast senescence in preeclampsia through interaction with and activation of the LMNA/p53 axis; elevated TIG1 reduces trophoblast invasion in a co-culture system.","method":"Co-immunoprecipitation (TIG1-LMNA), transcriptomic sequencing of TIG1-overexpressing cells, senescence marker analysis (p16/p21/p53), trophoblast invasion co-culture assay","journal":"Placenta","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP with functional correlation in disease context; single lab, limited mechanistic depth","pmids":["39756181"],"is_preprint":false},{"year":2024,"finding":"RARRES1 interacts with SPINK2 in hepatocellular carcinoma cells; RARRES1/SPINK2 co-expression suppresses HCC cell proliferation and migration and increases sensitivity to lenvatinib.","method":"Co-immunoprecipitation (RARRES1-SPINK2), gain- and loss-of-function overexpression/knockdown, proliferation and migration assays, in vivo tumor model","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional rescue in vivo; single lab","pmids":["38388961"],"is_preprint":false}],"current_model":"RARRES1 is a retinoic acid receptor (RARbeta/gamma)-responsive transmembrane protein that functions as a carboxypeptidase inhibitor: it binds and inhibits cytoplasmic carboxypeptidases AGBL2/CCP2 to regulate the alpha-tubulin tyrosination/deglutamylation cycle, which in turn modulates mitochondrial VDAC1 interactions, AMPK, and cellular energy metabolism; it is proteolytically cleaved in its extracellular domain (by MMP23 in podocytes) to generate a soluble form (sRARRES1) that is endocytosed by target cells where it inhibits RIOK1 to activate p53-mediated apoptosis (in podocytes) or binds KHDRBS1 to recruit Src kinase and phosphorylate STAT3, driving kidney fibrosis; it also stabilizes the receptor tyrosine kinase Axl and interacts with SPINK2 to suppress uPA-mediated invasion, and acts as a cell-surface determinant of proximal positional identity in salamander limb regeneration."},"narrative":{"teleology":[{"year":1996,"claim":"Identification of RARRES1 as a retinoic acid-responsive gene encoding a type II transmembrane glycoprotein established it as a retinoid-regulated effector in epithelial differentiation, resolving the question of which genes mediate RAR (not RXR) signaling in skin.","evidence":"Subtraction hybridization and retinoid-selective treatment in skin raft cultures with Northern/Southern blot validation","pmids":["8601727"],"confidence":"High","gaps":["Biochemical function of the large extracellular domain unknown","No target cell or pathway identified"]},{"year":2002,"claim":"Demonstration that RARRES1 overexpression suppresses invasiveness and tumorigenicity of prostate cancer cells established its functional identity as a tumor suppressor, framing all subsequent mechanistic work.","evidence":"Stable cDNA transfection in PC-3M cells with Matrigel invasion and nude mouse tumor growth assays","pmids":["11929948"],"confidence":"High","gaps":["Molecular target mediating invasion suppression unidentified","Endogenous loss-of-function not tested"]},{"year":2005,"claim":"Solving the latexin crystal structure and modeling RARRES1 onto it revealed a cystatin-fold architecture, predicting RARRES1 functions as a carboxypeptidase inhibitor — the first structural hypothesis for its mechanism.","evidence":"X-ray crystallography of mouse latexin at 1.83 Å with computational modeling of RARRES1","pmids":["15698574"],"confidence":"Medium","gaps":["RARRES1 carboxypeptidase inhibition not directly demonstrated","RARRES1 crystal structure not solved","Identity of cognate carboxypeptidase unknown"]},{"year":2011,"claim":"Discovery that RARRES1 directly binds AGBL2/CCP2 and that its depletion increases detyrosinated tubulin identified the cognate carboxypeptidase target and linked RARRES1 to microtubule posttranslational modification, validating the structural prediction.","evidence":"Co-immunoprecipitation of RARRES1-AGBL2 and siRNA knockdown with tyrosinated/detyrosinated tubulin Western blots","pmids":["21303978"],"confidence":"High","gaps":["Downstream cellular consequences of tubulin detyrosination via RARRES1 loss not mapped","Direct enzymatic inhibition kinetics not measured"]},{"year":2012,"claim":"Identification of CTCF as a positive transcriptional regulator of RARRES1 at the unmethylated proximal promoter explained how epigenetic silencing (promoter hypermethylation) extinguishes RARRES1 in cancer, and detection of secreted RARRES1 from neurofibroma Schwann cells established existence of a soluble form.","evidence":"ChIP for CTCF, bisulfite sequencing, CTCF siRNA; secretome proteomics of NF1-derived Schwann cells","pmids":["22615834","22942771"],"confidence":"Medium","gaps":["Whether soluble RARRES1 is biologically active not tested","Protease responsible for ectodomain cleavage unknown"]},{"year":2013,"claim":"Demonstration that RARRES1 stabilizes the receptor tyrosine kinase Axl by blocking its proteasomal degradation, thereby sustaining NF-κB/MMP-9 signaling in inflammatory breast cancer, revealed a second, carboxypeptidase-independent effector axis; concurrent localization data placed RARRES1 primarily in the endoplasmic reticulum.","evidence":"Co-IP of TIG1-Axl, siRNA with proteasome inhibitor rescue, immunofluorescence localization","pmids":["24014597","23588494"],"confidence":"High","gaps":["Whether Axl stabilization is direct or via an intermediate unknown","Reconciliation of ER localization with plasma membrane and secreted forms not addressed"]},{"year":2019,"claim":"Placement of RARRES1 in a linear pathway — CCP2 inhibition → tubulin glutamylation → VDAC1 regulation → mitochondrial membrane potential → AMPK — unified the tubulin and metabolic phenotypes and explained how RARRES1 loss promotes stem-like, anoikis-resistant states; in parallel, the RARRES1-SPINK2 interaction was shown to suppress uPA activity and EMT.","evidence":"Epistatic rescue experiments (CCP2 KD, VDAC1 inhibitor), mitochondrial assays, zebrafish metabolic phenotyping; Co-IP of TIG1-SPINK2 with SPINK2 knockdown rescue","pmids":["30899431","31886233"],"confidence":"High","gaps":["How tubulin glutamylation state affects VDAC1 interaction mechanistically unclear","Direct measurement of CCP2 enzymatic inhibition by RARRES1 still lacking"]},{"year":2020,"claim":"Discovery that soluble RARRES1 (sRARRES1), generated by ectodomain cleavage, is endocytosed and inhibits RIOK1 to activate p53-dependent podocyte apoptosis established sRARRES1 as a paracrine signaling molecule with a defined intracellular target, transforming understanding from a cell-autonomous suppressor to a secreted effector.","evidence":"Co-IP of sRARRES1-RIOK1, cleavage-site mutagenesis, podocyte-specific transgenic/knockout mice with albuminuria phenotype","pmids":["32634130"],"confidence":"High","gaps":["Identity of the cleavage protease not determined in this study","Whether RIOK1 inhibition occurs in non-kidney contexts untested"]},{"year":2022,"claim":"Constitutive Rarres1 knockout in mice resulting in follicular lymphoma and impaired B cell maturation provided definitive in vivo genetic evidence for tumor suppressor function, while salamander studies revealed RARRES1 as a cell-surface positional identity determinant governing proximo-distal patterning during limb regeneration.","evidence":"Rarres1-/- mouse model with tumor histopathology and flow cytometry; Tig1 overexpression/neutralization in axolotl blastema with scRNA-seq","pmids":["35541897","35241664"],"confidence":"High","gaps":["Whether lymphoma arises from tubulin-VDAC1-AMPK axis or another RARRES1 function not resolved","Mammalian relevance of positional identity function not established"]},{"year":2023,"claim":"Identification of VAC14 as a RARRES1 interactor mediating mTORC1/p70 S6K suppression via PI(3,5)P2 signaling added a phosphoinositide-dependent growth-inhibitory axis distinct from the CCP2-tubulin pathway.","evidence":"Co-IP of TIG1-VAC14, VAC14 knockdown epistasis abolishing TIG1's mTOR-inhibitory effect in melanoma cells","pmids":["37247911"],"confidence":"Medium","gaps":["Whether RARRES1 directly modulates PI(3,5)P2 levels or VAC14 stability not determined","Single cell type tested"]},{"year":2024,"claim":"Identification of MMP23 as the podocyte metalloproteinase generating sRARRES1, and discovery of the sRARRES1-KHDRBS1-Src-pSTAT3 fibrosis-driving pathway in tubular cells, completed the paracrine signaling model: MMP23 cleavage → sRARRES1 release → tubular uptake → KHDRBS1/Src-mediated STAT3 phosphorylation → fibrosis.","evidence":"scRNA-seq, AAV9-MMP23 knockdown in vivo, Co-IP with truncation mutants mapping sRARRES1-KHDRBS1-Src complex, proximal-tubule-specific Rarres1 KO in UUO/FA models, STAT3/Src pharmacological inhibition rescue","pmids":["38697478","41955023"],"confidence":"High","gaps":["Whether MMP23 is the sole RARRES1 sheddase outside the kidney is unknown","Structural basis of sRARRES1-KHDRBS1 interaction not resolved","Relationship between RIOK1-p53 and KHDRBS1-STAT3 axes in the same cell type not tested"]},{"year":null,"claim":"Key unresolved questions include: the crystal structure of RARRES1 itself, the direct enzymological measurement of CCP2 inhibition kinetics, how RARRES1 toggles between its multiple effector pathways (CCP2/tubulin vs. Axl vs. VAC14 vs. soluble RIOK1/KHDRBS1), the identity of RARRES1 sheddases in non-renal tissues, and whether the positional identity function in salamander regeneration is conserved in mammals.","evidence":"","pmids":[],"confidence":"Low","gaps":["No RARRES1 crystal or cryo-EM structure","No in vitro enzymatic inhibition assay for CCP2","Context-dependency of effector pathway selection not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,8,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,13,14,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,14,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,16,19]}],"complexes":[],"partners":["AGBL2","RIOK1","KHDRBS1","AXL","SPINK2","VAC14","MMP23B","LMNA"],"other_free_text":[]},"mechanistic_narrative":"RARRES1 (TIG1) is a retinoic acid receptor-responsive transmembrane protein that functions as a broad tumor suppressor and metabolic regulator by engaging distinct effector pathways in its membrane-bound and soluble forms. As a type II transmembrane carboxypeptidase inhibitor, RARRES1 binds and inhibits AGBL2/CCP2, thereby controlling alpha-tubulin deglutamylation, which in turn modulates mitochondrial VDAC1 interactions, AMPK activation, de novo lipogenesis, and anoikis resistance [PMID:21303978, PMID:30899431, PMID:30557378]; loss of Rarres1 in mice promotes follicular lymphoma and impairs B cell differentiation [PMID:35541897]. Proteolytic cleavage of RARRES1's extracellular domain by MMP23 generates a soluble form (sRARRES1) that is endocytosed by target cells, where it inhibits RIOK1 to activate p53-dependent podocyte apoptosis and glomerular injury, or binds KHDRBS1 to recruit Src kinase and phosphorylate STAT3 at Tyr705, driving kidney fibrosis [PMID:32634130, PMID:38697478, PMID:41955023]. RARRES1 additionally stabilizes the receptor tyrosine kinase Axl to regulate NF-κB/MMP-9-dependent invasion, interacts with SPINK2 to suppress uPA-mediated EMT, and inhibits mTORC1 signaling through VAC14 [PMID:24014597, PMID:31886233, PMID:37247911]."},"prefetch_data":{"uniprot":{"accession":"P49788","full_name":"Retinoic acid receptor responder protein 1","aliases":["Phorbol ester-induced gene 1 protein","PERG-1","RAR-responsive protein TIG1","Tazarotene-induced gene 1 protein"],"length_aa":294,"mass_kda":33.3,"function":"Inhibitor of the cytoplasmic carboxypeptidase AGBL2, may regulate the alpha-tubulin tyrosination cycle","subcellular_location":"Membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P49788/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RARRES1","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":[],"url":"https://opencell.sf.czbiohub.org/search/RARRES1","total_profiled":1310},"omim":[{"mim_id":"620677","title":"TRANSMEMBRANE PROTEIN 192; TMEM192","url":"https://www.omim.org/entry/620677"},{"mim_id":"617345","title":"ATP/GTP-BINDING PROTEIN-LIKE 2; AGBL2","url":"https://www.omim.org/entry/617345"},{"mim_id":"605090","title":"RETINOIC ACID RECEPTOR RESPONDER 1; RARRES1","url":"https://www.omim.org/entry/605090"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":233.7},{"tissue":"fallopian tube","ntpm":173.0},{"tissue":"salivary gland","ntpm":172.7}],"url":"https://www.proteinatlas.org/search/RARRES1"},"hgnc":{"alias_symbol":["TIG1","LXNL"],"prev_symbol":[]},"alphafold":{"accession":"P49788","domains":[{"cath_id":"3.10.450.10","chopping":"57-269","consensus_level":"medium","plddt":90.8326,"start":57,"end":269}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49788","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49788-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49788-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RARRES1","jax_strain_url":"https://www.jax.org/strain/search?query=RARRES1"},"sequence":{"accession":"P49788","fasta_url":"https://rest.uniprot.org/uniprotkb/P49788.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49788/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49788"}},"corpus_meta":[{"pmid":"1909121","id":"PMC_1909121","title":"Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1.","date":"1991","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1909121","citation_count":246,"is_preprint":false},{"pmid":"20675574","id":"PMC_20675574","title":"The tig1 histone deacetylase complex regulates infectious growth in the rice blast fungus Magnaporthe oryzae.","date":"2010","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/20675574","citation_count":124,"is_preprint":false},{"pmid":"8601727","id":"PMC_8601727","title":"Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor-responsive gene in skin.","date":"1996","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/8601727","citation_count":113,"is_preprint":false},{"pmid":"11929948","id":"PMC_11929948","title":"Tazarotene-induced gene 1 (TIG1) expression in prostate carcinomas and its relationship to tumorigenicity.","date":"2002","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/11929948","citation_count":88,"is_preprint":false},{"pmid":"32634130","id":"PMC_32634130","title":"Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32634130","citation_count":76,"is_preprint":false},{"pmid":"31002981","id":"PMC_31002981","title":"Natural Variations at TIG1 Encoding a TCP Transcription Factor Contribute to Plant Architecture Domestication in Rice.","date":"2019","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/31002981","citation_count":74,"is_preprint":false},{"pmid":"15698574","id":"PMC_15698574","title":"An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: relationship to cystatins and the tumor suppressor TIG1.","date":"2005","source":"Structure (London, England : 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to suppress the progression of kidney renal clear cell carcinoma.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36353618","citation_count":10,"is_preprint":false},{"pmid":"22669512","id":"PMC_22669512","title":"Identification of RARRES1 as a core regulator in liver fibrosis.","date":"2012","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/22669512","citation_count":10,"is_preprint":false},{"pmid":"22942771","id":"PMC_22942771","title":"Secretome survey of human plexiform neurofibroma derived Schwann Cells reveals a secreted form of the RARRES1 protein.","date":"2012","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22942771","citation_count":9,"is_preprint":false},{"pmid":"31632537","id":"PMC_31632537","title":"RARRES1 is a novel immune-related biomarker in GBM.","date":"2019","source":"American journal of translational 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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/24989270","citation_count":0,"is_preprint":false},{"pmid":"41955023","id":"PMC_41955023","title":"RARRES1 Promotes Tubular Fibrosis via the KHDRBS1/Src/p-STAT3 Axis.","date":"2026","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/41955023","citation_count":0,"is_preprint":false},{"pmid":"41854891","id":"PMC_41854891","title":"RARRES1 marks an immune-cold, chemoresistance-associated malignant epithelial subpopulation enriched in pancreatic ductal adenocarcinoma.","date":"2026","source":"Cancer immunology, immunotherapy : 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blot, RAR/RXR-selective retinoid treatment in skin raft cultures\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery with multiple orthogonal methods; foundational paper with 113 citations\",\n      \"pmids\": [\"8601727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIG1 overexpression in the highly malignant prostate cancer cell line PC-3M significantly decreased in vitro invasiveness and in vivo tumorigenicity, establishing a functional tumor suppressor role.\",\n      \"method\": \"cDNA transfection, in vitro Matrigel invasion assay, in vivo nude mouse tumor growth assay\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with defined cellular phenotypes in vitro and in vivo; 88 citations\",\n      \"pmids\": [\"11929948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The crystal structure of mouse latexin (the only known mammalian carboxypeptidase inhibitor and homolog of TIG1/RARRES1) was solved at 1.83 Å, revealing a cystatin fold architecture with pseudo-two-fold symmetry; modeling of TIG1 structure identified a putative membrane-binding surface, indicating RARRES1 is structurally related to carboxypeptidase inhibitors.\",\n      \"method\": \"X-ray crystallography (1.83 Å resolution), structural modeling\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 for latexin crystal structure; RARRES1 model is computational, reducing overall confidence\",\n      \"pmids\": [\"15698574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RARRES1 is a transmembrane carboxypeptidase inhibitor that directly interacts with AGBL2 (a cytoplasmic carboxypeptidase); knockdown of RARRES1 increases detyrosinated alpha-tubulin levels, consistent with RARRES1 acting as the cognate inhibitor of AGBL2 to regulate the tubulin tyrosination cycle and microtubule dynamics.\",\n      \"method\": \"Co-immunoprecipitation, AGBL2/RARRES1 siRNA knockdown, Western blot for tyrosinated/detyrosinated alpha-tubulin\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional interaction established by Co-IP and two independent knockdown experiments with specific biochemical readout; 57 citations\",\n      \"pmids\": [\"21303978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RARRES1 knockdown in prostatic epithelial cells downregulates PP2A, valosin-containing protein (VCP), and EB1, and upregulates DLG2 and Ankrd26, placing RARRES1 upstream of multiple signaling nodes involved in growth regulation, autophagy, and spindle dynamics.\",\n      \"method\": \"siRNA knockdown, 2D-DIGE proteomics, MALDI mass spectrometry, Western blot\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus Western blot validation, single lab\",\n      \"pmids\": [\"20842219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TIG1/RARRES1 interacts with the receptor tyrosine kinase Axl, stabilizing Axl by inhibiting its proteasome-dependent degradation; TIG1 depletion reduces Axl expression, inactivates NF-κB, and downregulates MMP-9, thereby regulating invasion of inflammatory breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (TIG1-Axl interaction), siRNA depletion, Western blot for Axl/NF-κB/MMP-9, in vitro invasion/migration assays, in vivo tumor growth\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional rescue and in vivo validation in a single study; 68 citations\",\n      \"pmids\": [\"24014597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RARRES1 resides primarily in the endoplasmic reticulum (not the plasma membrane), whereas its homolog LXN is nuclear; siRNA suppression of RARRES1 enhances colony-forming ability and invasive capacity of primary prostate epithelial cultures, and all-trans retinoic acid induces RARRES1 expression coordinately with differentiation.\",\n      \"method\": \"Immunofluorescence subcellular localization, siRNA knockdown, colony-forming assay, Matrigel invasion assay, retinoic acid treatment\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence plus loss-of-function phenotype; single lab\",\n      \"pmids\": [\"23588494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Epigenetic silencing of RARRES1 is mediated by hypermethylation specifically at a proximal promoter element, and CTCF binds to the unmethylated promoter to positively regulate RARRES1 transcription; CTCF knockdown suppresses RARRES1 expression.\",\n      \"method\": \"Bisulfite sequencing, methylation-specific PCR, chromatin immunoprecipitation (CTCF), CTCF siRNA knockdown, reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional knockdown with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"22615834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RARRES1 interaction with cytoplasmic carboxypeptidase CCP2 inhibits tubulin deglutamylation, which in turn regulates mitochondrial VDAC1 interactions, mitochondrial membrane potential, and AMPK activation; depletion of RARRES1 increases stem cell markers and anoikis resistance, effects reversed by CCP2 depletion or VDAC1 inhibition.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown (RARRES1, CCP2), VDAC1 inhibitor treatment, mitochondrial membrane potential assay, AMPK/energy balance assays, zebrafish metabolic phenotyping\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placed by epistasis (CCP2/VDAC1 rescue), multiple orthogonal methods, in vivo zebrafish validation\",\n      \"pmids\": [\"30899431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Soluble RARRES1, generated by proteolytic cleavage of its extracellular domain, is endocytosed by podocytes and interacts with and inhibits RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis; mutation of the cleavage site abolishes the apoptotic effect, and podocyte-specific RARRES1 overexpression in mice causes glomerular injury and albuminuria.\",\n      \"method\": \"Co-immunoprecipitation (sRARRES1-RIOK1), cleavage-site mutagenesis, podocyte endocytosis assay, apoptosis assay, podocyte-specific transgenic/knockout mice, transcriptomic analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP, mutagenesis, in vitro apoptosis assay, and in vivo mouse models with specific phenotype; 76 citations\",\n      \"pmids\": [\"32634130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RARRES1 depletion in epithelial cells causes global increase in lipid synthesis via de novo lipogenesis (DNL) by rewiring glucose metabolism; the increase in fatty acid availability supports mitochondrial fatty acid oxidation during starvation; RARRES1 expression is regulated by PPAR signaling.\",\n      \"method\": \"Non-targeted LC-MS lipidomics, FASN inhibitor (C75) rescue experiment, metabolic flux analysis, siRNA knockdown in breast and prostate epithelial cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-method metabolomics with pharmacological rescue; single lab\",\n      \"pmids\": [\"30557378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RARRES1 overexpression in prostate cancer cell lines represses MAPK activation, induces autophagy (increases beclin, ATG3, LC3B-II), elevates SIRT1, inhibits mTOR, increases catalase, and inhibits angiogenesis in endothelial cells.\",\n      \"method\": \"cDNA overexpression, Western blot (autophagy markers, SIRT1, mTOR pathway), endothelial tube formation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with Western blot readouts, single lab, no epistatic rescue or mechanistic target identification\",\n      \"pmids\": [\"28678839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIG1/RARRES1 interacts with serine protease inhibitor SPINK2 in NT2/D1 testicular carcinoma cells; SPINK2 enhances TIG1-mediated suppression of uPA activity and EMT, while SPINK2 silencing alleviates TIG1-mediated cell migration and invasion suppression.\",\n      \"method\": \"Co-immunoprecipitation (TIG1-SPINK2), siRNA knockdown of SPINK2, uPA activity assay, EMT marker Western blot, migration and invasion assays\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional epistasis via SPINK2 knockdown rescue; single lab\",\n      \"pmids\": [\"31886233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Matrix metalloproteinase 23 (MMP23) is the podocyte-specific metalloproteinase responsible for cleaving RARRES1 to generate soluble RARRES1 (sRARRES1); AAV9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo and prevented RARRES1-driven glomerular and tubular injury.\",\n      \"method\": \"scRNA-seq to identify MMP23 expression, AAV9-mediated MMP23 knockdown in vivo, RARRES1 cleavage-mutant overexpression, histological assessment of kidney injury\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic knockdown with specific mechanistic readout, cleavage mutant controls, multiple CKD models\",\n      \"pmids\": [\"38697478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"sRARRES1 (soluble RARRES1) directly taken up by proximal tubular epithelial cells binds KHDRBS1, recruits Src kinase, and induces STAT3 phosphorylation at Tyr705, upregulating pro-fibrotic factors; proximal-tubule-specific Rarres1 knockout reduces kidney fibrosis, and STAT3/Src inhibition reverses the fibrotic phenotype.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation with truncation mutants (sRARRES1-KHDRBS1-Src-pSTAT3), proximal-tubule-specific knockout mice (UUO and folic acid models), RARRES1-overexpressing mice, pharmacological STAT3/Src inhibition\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS identification, Co-IP with domain mapping, in vivo genetic KO and OE with multiple CKD models, pharmacological rescue\",\n      \"pmids\": [\"41955023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIG1/RARRES1 interacts with VAC14 and inhibits insulin-induced mTORC1-p70 S6K activation in melanoma cells; TIG1 had no additional inhibitory effect on mTOR signaling in the absence of VAC14, indicating TIG1 suppresses mTOR primarily through VAC14, affecting PI(3,5)P2 rather than PI(4,5)P2 signaling.\",\n      \"method\": \"Co-immunoprecipitation (TIG1-VAC14), VAC14 knockdown epistasis, Western blot for mTORC1/p70 S6K/pAKT, cell proliferation assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus genetic epistasis via VAC14 knockdown; single lab\",\n      \"pmids\": [\"37247911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of Rarres1 in mice promotes follicular lymphoma development and impairs B cell activation, maturation, and differentiation into plasma cells; Rarres1-/- embryonic fibroblasts recapitulate in vitro defects in tubulin glutamylation and cell metabolism, confirming RARRES1 as a bona fide in vivo tumor suppressor.\",\n      \"method\": \"Constitutive Rarres1 knockout mouse model, flow cytometry (B cell differentiation), tumor histopathology, tubulin glutamylation assay, metabolic assays in primary fibroblasts\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO mouse with specific tumor phenotype and mechanistic recapitulation in primary cells\",\n      \"pmids\": [\"35541897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tig1/Rarres1 acts as a cell-surface determinant of proximal positional identity during salamander limb regeneration; its overexpression causes proximal displacement of blastema cells and regeneration defects in distal elements, upregulates Prod1, and inhibits Hoxa13 and distal transcriptional networks.\",\n      \"method\": \"Single-cell RNA-seq, Tig1 overexpression and neutralization in salamander blastema, in situ hybridization for Prod1/Hoxa13, proximo-distal cell surface interaction assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with specific positional identity readout in salamander; ortholog functional context consistent with mammalian RARRES1\",\n      \"pmids\": [\"35241664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RARRES1 protein is secreted (as a soluble form) by NF1-derived plexiform neurofibroma Schwann cells but not by normal Schwann cells; all-trans retinoic acid modulates RARRES1 secretion in a dose-dependent manner.\",\n      \"method\": \"Secretome proteomics (SDS-PAGE + LC-MS/MS), conditioned media analysis, retinoic acid dose-response\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics-based identification of secreted form with dose-dependent retinoic acid regulation; single lab\",\n      \"pmids\": [\"22942771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RARRES1 expression in basal-like triple-negative breast cancer is maintained by promoter hypomethylation and is driven by ALDH1A3-generated retinoic acid acting as RAR ligand; RARRES1 functions as a tumor suppressor in TNBC as shown by cell proliferation and tumor growth assays.\",\n      \"method\": \"Illumina HumanMethylation450 arrays, chromatin immunoprecipitation, siRNA/overexpression, cell proliferation assay, in vivo tumor growth\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus methylation arrays and functional assays establishing ALDH1A3-RA-RARRES1 regulatory axis; single lab\",\n      \"pmids\": [\"27286452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TIG1/RARRES1 induces trophoblast senescence in preeclampsia through interaction with and activation of the LMNA/p53 axis; elevated TIG1 reduces trophoblast invasion in a co-culture system.\",\n      \"method\": \"Co-immunoprecipitation (TIG1-LMNA), transcriptomic sequencing of TIG1-overexpressing cells, senescence marker analysis (p16/p21/p53), trophoblast invasion co-culture assay\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional correlation in disease context; single lab, limited mechanistic depth\",\n      \"pmids\": [\"39756181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RARRES1 interacts with SPINK2 in hepatocellular carcinoma cells; RARRES1/SPINK2 co-expression suppresses HCC cell proliferation and migration and increases sensitivity to lenvatinib.\",\n      \"method\": \"Co-immunoprecipitation (RARRES1-SPINK2), gain- and loss-of-function overexpression/knockdown, proliferation and migration assays, in vivo tumor model\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional rescue in vivo; single lab\",\n      \"pmids\": [\"38388961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RARRES1 is a retinoic acid receptor (RARbeta/gamma)-responsive transmembrane protein that functions as a carboxypeptidase inhibitor: it binds and inhibits cytoplasmic carboxypeptidases AGBL2/CCP2 to regulate the alpha-tubulin tyrosination/deglutamylation cycle, which in turn modulates mitochondrial VDAC1 interactions, AMPK, and cellular energy metabolism; it is proteolytically cleaved in its extracellular domain (by MMP23 in podocytes) to generate a soluble form (sRARRES1) that is endocytosed by target cells where it inhibits RIOK1 to activate p53-mediated apoptosis (in podocytes) or binds KHDRBS1 to recruit Src kinase and phosphorylate STAT3, driving kidney fibrosis; it also stabilizes the receptor tyrosine kinase Axl and interacts with SPINK2 to suppress uPA-mediated invasion, and acts as a cell-surface determinant of proximal positional identity in salamander limb regeneration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RARRES1 (TIG1) is a retinoic acid receptor-responsive transmembrane protein that functions as a broad tumor suppressor and metabolic regulator by engaging distinct effector pathways in its membrane-bound and soluble forms. As a type II transmembrane carboxypeptidase inhibitor, RARRES1 binds and inhibits AGBL2/CCP2, thereby controlling alpha-tubulin deglutamylation, which in turn modulates mitochondrial VDAC1 interactions, AMPK activation, de novo lipogenesis, and anoikis resistance [PMID:21303978, PMID:30899431, PMID:30557378]; loss of Rarres1 in mice promotes follicular lymphoma and impairs B cell differentiation [PMID:35541897]. Proteolytic cleavage of RARRES1's extracellular domain by MMP23 generates a soluble form (sRARRES1) that is endocytosed by target cells, where it inhibits RIOK1 to activate p53-dependent podocyte apoptosis and glomerular injury, or binds KHDRBS1 to recruit Src kinase and phosphorylate STAT3 at Tyr705, driving kidney fibrosis [PMID:32634130, PMID:38697478, PMID:41955023]. RARRES1 additionally stabilizes the receptor tyrosine kinase Axl to regulate NF-κB/MMP-9-dependent invasion, interacts with SPINK2 to suppress uPA-mediated EMT, and inhibits mTORC1 signaling through VAC14 [PMID:24014597, PMID:31886233, PMID:37247911].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of RARRES1 as a retinoic acid-responsive gene encoding a type II transmembrane glycoprotein established it as a retinoid-regulated effector in epithelial differentiation, resolving the question of which genes mediate RAR (not RXR) signaling in skin.\",\n      \"evidence\": \"Subtraction hybridization and retinoid-selective treatment in skin raft cultures with Northern/Southern blot validation\",\n      \"pmids\": [\"8601727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical function of the large extracellular domain unknown\", \"No target cell or pathway identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that RARRES1 overexpression suppresses invasiveness and tumorigenicity of prostate cancer cells established its functional identity as a tumor suppressor, framing all subsequent mechanistic work.\",\n      \"evidence\": \"Stable cDNA transfection in PC-3M cells with Matrigel invasion and nude mouse tumor growth assays\",\n      \"pmids\": [\"11929948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target mediating invasion suppression unidentified\", \"Endogenous loss-of-function not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Solving the latexin crystal structure and modeling RARRES1 onto it revealed a cystatin-fold architecture, predicting RARRES1 functions as a carboxypeptidase inhibitor — the first structural hypothesis for its mechanism.\",\n      \"evidence\": \"X-ray crystallography of mouse latexin at 1.83 Å with computational modeling of RARRES1\",\n      \"pmids\": [\"15698574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RARRES1 carboxypeptidase inhibition not directly demonstrated\", \"RARRES1 crystal structure not solved\", \"Identity of cognate carboxypeptidase unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that RARRES1 directly binds AGBL2/CCP2 and that its depletion increases detyrosinated tubulin identified the cognate carboxypeptidase target and linked RARRES1 to microtubule posttranslational modification, validating the structural prediction.\",\n      \"evidence\": \"Co-immunoprecipitation of RARRES1-AGBL2 and siRNA knockdown with tyrosinated/detyrosinated tubulin Western blots\",\n      \"pmids\": [\"21303978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream cellular consequences of tubulin detyrosination via RARRES1 loss not mapped\", \"Direct enzymatic inhibition kinetics not measured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of CTCF as a positive transcriptional regulator of RARRES1 at the unmethylated proximal promoter explained how epigenetic silencing (promoter hypermethylation) extinguishes RARRES1 in cancer, and detection of secreted RARRES1 from neurofibroma Schwann cells established existence of a soluble form.\",\n      \"evidence\": \"ChIP for CTCF, bisulfite sequencing, CTCF siRNA; secretome proteomics of NF1-derived Schwann cells\",\n      \"pmids\": [\"22615834\", \"22942771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether soluble RARRES1 is biologically active not tested\", \"Protease responsible for ectodomain cleavage unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that RARRES1 stabilizes the receptor tyrosine kinase Axl by blocking its proteasomal degradation, thereby sustaining NF-κB/MMP-9 signaling in inflammatory breast cancer, revealed a second, carboxypeptidase-independent effector axis; concurrent localization data placed RARRES1 primarily in the endoplasmic reticulum.\",\n      \"evidence\": \"Co-IP of TIG1-Axl, siRNA with proteasome inhibitor rescue, immunofluorescence localization\",\n      \"pmids\": [\"24014597\", \"23588494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Axl stabilization is direct or via an intermediate unknown\", \"Reconciliation of ER localization with plasma membrane and secreted forms not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placement of RARRES1 in a linear pathway — CCP2 inhibition → tubulin glutamylation → VDAC1 regulation → mitochondrial membrane potential → AMPK — unified the tubulin and metabolic phenotypes and explained how RARRES1 loss promotes stem-like, anoikis-resistant states; in parallel, the RARRES1-SPINK2 interaction was shown to suppress uPA activity and EMT.\",\n      \"evidence\": \"Epistatic rescue experiments (CCP2 KD, VDAC1 inhibitor), mitochondrial assays, zebrafish metabolic phenotyping; Co-IP of TIG1-SPINK2 with SPINK2 knockdown rescue\",\n      \"pmids\": [\"30899431\", \"31886233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How tubulin glutamylation state affects VDAC1 interaction mechanistically unclear\", \"Direct measurement of CCP2 enzymatic inhibition by RARRES1 still lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that soluble RARRES1 (sRARRES1), generated by ectodomain cleavage, is endocytosed and inhibits RIOK1 to activate p53-dependent podocyte apoptosis established sRARRES1 as a paracrine signaling molecule with a defined intracellular target, transforming understanding from a cell-autonomous suppressor to a secreted effector.\",\n      \"evidence\": \"Co-IP of sRARRES1-RIOK1, cleavage-site mutagenesis, podocyte-specific transgenic/knockout mice with albuminuria phenotype\",\n      \"pmids\": [\"32634130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cleavage protease not determined in this study\", \"Whether RIOK1 inhibition occurs in non-kidney contexts untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Constitutive Rarres1 knockout in mice resulting in follicular lymphoma and impaired B cell maturation provided definitive in vivo genetic evidence for tumor suppressor function, while salamander studies revealed RARRES1 as a cell-surface positional identity determinant governing proximo-distal patterning during limb regeneration.\",\n      \"evidence\": \"Rarres1-/- mouse model with tumor histopathology and flow cytometry; Tig1 overexpression/neutralization in axolotl blastema with scRNA-seq\",\n      \"pmids\": [\"35541897\", \"35241664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lymphoma arises from tubulin-VDAC1-AMPK axis or another RARRES1 function not resolved\", \"Mammalian relevance of positional identity function not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of VAC14 as a RARRES1 interactor mediating mTORC1/p70 S6K suppression via PI(3,5)P2 signaling added a phosphoinositide-dependent growth-inhibitory axis distinct from the CCP2-tubulin pathway.\",\n      \"evidence\": \"Co-IP of TIG1-VAC14, VAC14 knockdown epistasis abolishing TIG1's mTOR-inhibitory effect in melanoma cells\",\n      \"pmids\": [\"37247911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RARRES1 directly modulates PI(3,5)P2 levels or VAC14 stability not determined\", \"Single cell type tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of MMP23 as the podocyte metalloproteinase generating sRARRES1, and discovery of the sRARRES1-KHDRBS1-Src-pSTAT3 fibrosis-driving pathway in tubular cells, completed the paracrine signaling model: MMP23 cleavage → sRARRES1 release → tubular uptake → KHDRBS1/Src-mediated STAT3 phosphorylation → fibrosis.\",\n      \"evidence\": \"scRNA-seq, AAV9-MMP23 knockdown in vivo, Co-IP with truncation mutants mapping sRARRES1-KHDRBS1-Src complex, proximal-tubule-specific Rarres1 KO in UUO/FA models, STAT3/Src pharmacological inhibition rescue\",\n      \"pmids\": [\"38697478\", \"41955023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MMP23 is the sole RARRES1 sheddase outside the kidney is unknown\", \"Structural basis of sRARRES1-KHDRBS1 interaction not resolved\", \"Relationship between RIOK1-p53 and KHDRBS1-STAT3 axes in the same cell type not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the crystal structure of RARRES1 itself, the direct enzymological measurement of CCP2 inhibition kinetics, how RARRES1 toggles between its multiple effector pathways (CCP2/tubulin vs. Axl vs. VAC14 vs. soluble RIOK1/KHDRBS1), the identity of RARRES1 sheddases in non-renal tissues, and whether the positional identity function in salamander regeneration is conserved in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No RARRES1 crystal or cryo-EM structure\", \"No in vitro enzymatic inhibition assay for CCP2\", \"Context-dependency of effector pathway selection not addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 8, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 13, 14, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 14, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 16, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AGBL2\",\n      \"RIOK1\",\n      \"KHDRBS1\",\n      \"AXL\",\n      \"SPINK2\",\n      \"VAC14\",\n      \"MMP23B\",\n      \"LMNA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}