Affinage

RARRES1

Retinoic acid receptor responder protein 1 · UniProt P49788

Length
294 aa
Mass
33.3 kDa
Annotated
2026-06-10
27 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RARRES1 is a transmembrane carboxypeptidase inhibitor that acts as a tumor suppressor and a regulator of cellular metabolism, microtubule modification, and apoptosis (PMID:21303978, PMID:23588494, PMID:27286452). In the cytoplasmic compartment it binds and inhibits the tubulin-modifying carboxypeptidases AGBL2 and CCP2, thereby controlling α-tubulin detyrosination and deglutamylation; through CCP2 this activity is relayed to the mitochondrial channel VDAC1, mitochondrial membrane potential, and AMPK to set cellular energy balance and survival (PMID:21303978, PMID:30899431). RARRES1 localizes principally to the endoplasmic reticulum in epithelial cells, where its loss enhances colony formation and invasion (PMID:23588494). A distinct extracellular mechanism operates after proteolysis: MMP23 cleaves RARRES1 to a soluble form (sRARRES1) that is endocytosed by podocytes and proximal tubular cells, where it binds and inhibits RIO kinase 1 (RIOK1), activating p53 and driving apoptosis and glomerular/tubular injury — an effect abolished by mutation of the cleavage site (PMID:32634130, PMID:38697478). RARRES1 also constrains lipid metabolism, since its depletion shifts cells toward glucose-dependent de novo lipogenesis reversible by FASN inhibition, and sRARRES1 uptake promotes tubular lipid accumulation (PMID:38697478, PMID:30557378). Its transcription is driven by retinoic acid signaling via ALDH1A3 and by CTCF binding at an unmethylated proximal promoter, the element silenced by hypermethylation in breast cancer (PMID:22615834, PMID:27286452). Loss of Rarres1 in mice causes follicular lymphoma and impairs B-cell maturation while increasing B-cell survival (PMID:35541897).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2010 Low

    Before any defined molecular partners were known, an unbiased proteomic screen began mapping the protein-level consequences of RARRES1 loss in prostate epithelium, establishing that it influences phosphatase, autophagy, and cytoskeletal regulators.

    Evidence siRNA knockdown with DIGE/MALDI mass spectrometry and western blot in prostate epithelial cells

    PMID:20842219

    Open questions at the time
    • Correlative proteomic changes only, no direct interaction or epistasis
    • Does not establish which changes are primary versus downstream
    • No mechanism linking RARRES1 to the affected proteins
  2. 2011 Medium

    The first defined molecular activity for RARRES1 was established by showing it binds and inhibits the tubulin carboxypeptidase AGBL2, placing it in the α-tubulin tyrosination cycle.

    Evidence Co-IP/interaction assay plus siRNA knockdown with detyrosinated α-tubulin western readout (Cancer Research)

    PMID:21303978

    Open questions at the time
    • Single lab
    • Functional consequence of altered detyrosination for tumor suppression not resolved
    • No structural basis for inhibition
  3. 2012 Medium

    Two complementary studies established how RARRES1 expression is controlled — positively by CTCF binding at an unmethylated proximal promoter and silenced by promoter hypermethylation — and that the protein can be released as a secreted form under retinoic acid control.

    Evidence ChIP, methylation mapping and CTCF knockdown in breast cancer; conditioned-media LC-MS/MS secretome with ATRA dose-response in NF1 Schwann cells

    PMID:22615834 PMID:22942771

    Open questions at the time
    • Secretion finding is Low-confidence detection without functional follow-up
    • Mechanism connecting CTCF loss to methylation not defined
    • Relationship between ER residence and secretion unresolved
  4. 2013 Medium

    The subcellular localization was revised, showing RARRES1 resides in the ER rather than the plasma membrane, with knockdown enhancing transformed phenotypes — refining where its inhibitory activity is exerted.

    Evidence Subcellular fractionation/immunofluorescence with colony-formation and invasion assays in primary prostate cultures

    PMID:23588494

    Open questions at the time
    • Single lab
    • Does not reconcile ER residence with cytoplasmic carboxypeptidase targets
    • Mechanism of invasion suppression not defined
  5. 2016 Medium

    RARRES1 was shown to be maintained in basal-like TNBC via promoter hypomethylation and ALDH1A3-driven retinoic acid signaling, linking its transcriptional control directly to tumor-suppressor function.

    Evidence Methylation arrays, ChIP, and proliferation/tumor growth assays across a 26-cell-line panel

    PMID:27286452

    Open questions at the time
    • Subtype-specific regulation may not generalize
    • Downstream effector of suppression not identified here
    • Single lab
  6. 2018 Medium

    Metabolomics established a metabolic role: RARRES1 loss drives a switch to glucose-dependent de novo lipogenesis, reversible by FASN inhibition, tying the gene to lipid synthesis control.

    Evidence Non-targeted LC-MS metabolomics with C75/FASN inhibitor rescue and PPAR pathway analysis

    PMID:30557378

    Open questions at the time
    • Mechanistic link between RARRES1 and lipogenic enzymes not delineated
    • Single lab
    • PPAR regulation correlative
  7. 2019 Medium

    Epistasis experiments connected RARRES1's tubulin-modifying activity to mitochondrial energy control, showing CCP2 inhibition feeds through VDAC1 to membrane potential and AMPK.

    Evidence CCP2 depletion and VDAC1 inhibition rescue of RARRES1-depletion phenotype, tubulin glutamylation, membrane potential and AMPK assays, zebrafish model (Oncotarget)

    PMID:30899431

    Open questions at the time
    • Single lab
    • Direct physical chain from tubulin modification to VDAC1 not shown
    • Generalizability across cell types unclear
  8. 2020 High

    A cleavage-dependent extracellular mechanism was defined: soluble RARRES1 is endocytosed by podocytes and inhibits RIOK1 to activate p53 and trigger apoptosis, with the cleavage site required for in vivo glomerular injury.

    Evidence Cleavage-site mutagenesis, endocytosis assay, RARRES1–RIOK1 Co-IP, p53/apoptosis assays, and podocyte-specific transgenic and knockdown mouse models (JCI)

    PMID:32634130

    Open questions at the time
    • Identity of the cleaving protease not established in this study
    • Structural basis of RIOK1 inhibition unknown
    • Relationship to the cytoplasmic carboxypeptidase mechanism unclear
  9. 2022 Medium

    A constitutive knockout established RARRES1 as a tumor suppressor in vivo, causing follicular lymphoma and impaired B-cell maturation while confirming tubulin/metabolic phenotypes in fibroblasts; parallel studies reported candidate partners ICAM1 and SPINK2.

    Evidence Two-strain knockout mice with B-cell, UPR/HSR, tubulin glutamylation and metabolic assays; co-culture and Co-IP partner studies in renal and hepatocellular carcinoma

    PMID:35541897 PMID:36353618

    Open questions at the time
    • ICAM1 interaction lacks a direct binding assay (Low-confidence)
    • Mechanism linking B-cell survival to lymphomagenesis incomplete
    • How tubulin/metabolic axis drives the in vivo phenotype unresolved
  10. 2024 High

    The protease generating soluble RARRES1 was identified as MMP23, and sRARRES1 uptake was shown to cause proximal tubular injury and lipid accumulation, completing the cleavage-uptake-injury axis in kidney; an SPINK2 interaction was reported in HCC.

    Evidence scRNA-seq identification of MMP23, AAV9 in vivo knockdown, cleavage-mutant comparisons across kidney disease models; Co-IP and functional assays for SPINK2 in HCC

    PMID:38388961 PMID:38697478

    Open questions at the time
    • SPINK2 interaction is Low-confidence single Co-IP
    • Molecular pathway from sRARRES1 uptake to lipid deregulation not fully resolved
    • Whether MMP23 cleaves RARRES1 in non-kidney tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RARRES1's ER-localized carboxypeptidase-inhibitor activity, its cytoplasmic tubulin/mitochondrial axis, and its cleavage-dependent extracellular RIOK1/p53 apoptotic axis are integrated into a single coherent function remains unresolved.
  • No structural model of RARRES1 or its inhibitory complexes
  • Whether the cytoplasmic and extracellular mechanisms operate in the same cells is unknown
  • Direct RARRES1 substrates/targets beyond carboxypeptidases not enumerated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AGBL2CCP2ICAM1LCN2MMP23RIOK1SPINK2VDAC1

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 RARRES1 is a transmembrane carboxypeptidase inhibitor that interacts with AGBL2 (a cytoplasmic carboxypeptidase/tubulin tyrosine carboxypeptidase). Knockdown of RARRES1 increases detyrosinated α-tubulin, consistent with RARRES1 acting as the cognate inhibitor of AGBL2 in the α-tubulin tyrosination cycle. Co-immunoprecipitation/interaction assay, siRNA knockdown with western blot readout of detyrosinated α-tubulin Cancer research Medium 21303978
2019 RARRES1 interacts with cytoplasmic carboxypeptidase 2 (CCP2) to inhibit tubulin deglutamylation; this in turn regulates the mitochondrial voltage-dependent anion channel (VDAC1), mitochondrial membrane potential, and AMPK activation, thereby controlling energy balance and cell survival. Depletion of CCP2 or inhibition of VDAC1 reverses the metabolic effects of RARRES1 depletion. Genetic epistasis (CCP2 depletion, VDAC1 inhibition rescuing RARRES1-depletion phenotype), tubulin glutamylation assays, mitochondrial membrane potential measurement, AMPK activation assays, zebrafish metabolic phenotype Oncotarget Medium 30899431
2020 Soluble RARRES1 (generated by extracellular domain cleavage) 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. Podocyte-specific overexpression of RARRES1 in mice causes glomerular injury and albuminuria, while the cleavage mutant has no effect; podocyte-specific knockdown ameliorates adriamycin-induced nephropathy. Cleavage-site mutagenesis, endocytosis assay, Co-immunoprecipitation (RARRES1–RIOK1), p53 activation measurement, in vitro apoptosis assay, podocyte-specific transgenic/knockdown mouse models with functional kidney readouts The Journal of clinical investigation High 32634130
2013 RARRES1 resides primarily in the endoplasmic reticulum (not at the plasma membrane as previously supposed), whereas its homologue LXN is located in the nucleus of prostate epithelial cells. siRNA suppression of RARRES1 enhances colony-forming ability and invasive capacity of primary prostate cultures. Subcellular fractionation/immunofluorescence localization, siRNA knockdown with colony-formation and invasion assays Oncogenesis Medium 23588494
2012 CTCF binds the unmethylated proximal RARRES1 promoter and positively regulates RARRES1 transcription; knockdown of CTCF reduces RARRES1 expression. Hypermethylation of the proximal promoter element (not the upstream region) is responsible for silencing RARRES1 transcription in breast cancer. Chromatin immunoprecipitation (ChIP), promoter methylation mapping, siRNA knockdown of CTCF with RARRES1 expression readout, promoter activity assays PloS one Medium 22615834
2024 Matrix metalloproteinase 23 (MMP23) is the podocyte-specific metalloproteinase responsible for cleaving RARRES1 into its soluble form (sRARRES1). AAV9-mediated knockdown of MMP23 in vivo abrogates sRARRES1 uptake in tubular cells. sRARRES1 is taken up by proximal tubules and causes tubular injury, vacuolation, and lipid accumulation via deregulation of lipid metabolism. MMP23 identification by single-cell RNA-seq, AAV9-mediated in vivo knockdown of MMP23 with functional readout (sRARRES1 uptake, tubular injury), cleavage mutant comparison in multiple mouse models of kidney disease Kidney international High 38697478
2018 RARRES1 depletion in epithelial cells causes a global increase in lipid synthesis, switching glucose metabolism from aerobic glycolysis to glucose-dependent de novo lipogenesis (DNL). Inhibition of FASN with C75 reverses the effects of RARRES1 depletion. RARRES1 is regulated by PPAR signaling. Non-targeted LC-MS metabolomics, FASN inhibitor rescue experiment, gene expression analysis PloS one Medium 30557378
2017 Overexpression of RARRES1 in prostate cancer cell lines represses MAPK activation, induces autophagy-related genes (beclin, ATG3, LC3B-II conversion), increases SIRT1 levels, inhibits mTOR, elevates catalase, and inhibits angiogenesis in endothelial cells. Overexpression studies with western blot for MAPK, autophagy markers, SIRT1, mTOR, catalase; endothelial cell angiogenesis assay PloS one Low 28678839
2010 Knockdown of RARRES1 in prostate epithelial cells downregulates PP2A, downregulates valosin-containing protein (VCP, causing impaired autophagy), downregulates EB1, upregulates DLG2, and upregulates Ankrd26. siRNA knockdown, differential in-gel electrophoresis (DIGE), MALDI mass spectrometry, western blot Journal of Cancer Low 20842219
2012 RARRES1 is secreted in soluble form by NF1-derived Schwann cells (but not normal Schwann cells), and all-trans retinoic acid modulates its secretion in a dose-dependent manner, demonstrating that RARRES1 can be released as a secreted protein. Conditioned media LC-MS/MS secretome analysis, dose-response treatment with all-trans retinoic acid International journal of molecular sciences Low 22942771
2022 RARRES1 interacts with ICAM1 in kidney renal clear cell carcinoma cells; RARRES1 enhances ICAM1 expression, which induces M1 macrophage activation and decreases cancer cell viability. Co-culture of cancer cells with THP-1 macrophages, immunofluorescence, gene expression analysis, cell viability and apoptosis assays Frontiers in immunology Low 36353618
2022 Constitutive Rarres1 knockout mice develop follicular lymphoma in a dose-dependent manner. Loss of RARRES1 in B cells impairs activation, maturation, differentiation into plasma cells, and cell cycle progression, while increasing B cell survival and activating the unfolded protein response (UPR) and heat shock response (HSR). In fibroblasts, RARRES1 loss increases bioenergetic capacity and recapitulates tubulin glutamylation and metabolic phenotypes seen in vitro. Constitutive knockout mouse model (two strains), B cell functional assays, UPR/HSR pathway analysis, tubulin glutamylation measurement, metabolic profiling of fibroblasts International journal of biological sciences Medium 35541897
2024 RARRES1 interacts with SPINK2 (serine protease inhibitor Kazal-type 2) in hepatocellular carcinoma cells, as demonstrated by co-immunoprecipitation. Both proteins suppress HCC proliferation, migration, and increase sensitivity to lenvatinib. Co-immunoprecipitation, gain- and loss-of-function experiments (overexpression and siRNA), in vitro and in vivo tumor growth assays Biology direct Low 38388961
2016 In basal-like triple-negative breast cancer, RARRES1 expression is maintained through promoter hypomethylation combined with retinoic acid signaling driven by ALDH1A3 (which produces the retinoic acid ligand). Chromatin immunoprecipitation confirmed retinoic acid-mediated transcriptional regulation of RARRES1 in this subtype. RARRES1 functions as a tumor suppressor in TNBC as shown by cell proliferation and tumor growth assays. Illumina HumanMethylation450 arrays, chromatin immunoprecipitation, cell proliferation assays, tumor growth assays, 26-cell line expression panel Oncotarget Medium 27286452
2023 RARRES1 interacts with LCN2 (lipocalin-2) in podocytes; co-expression of RARRES1 and LCN2 contributes to angiotensin II-induced podocyte apoptosis and dysfunction. Inhibiting RARRES1 and LCN2 expression (e.g., with astragalus polysaccharide) alleviates podocyte injury. Binding prediction validated by co-immunoprecipitation/interaction assay, overexpression vectors, cell viability and apoptosis assays, in vivo angiotensin II mouse model Clinical and experimental pharmacology & physiology Low 36876579

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression. The Journal of clinical investigation 76 32634130
2011 Tumor suppressor RARRES1 interacts with cytoplasmic carboxypeptidase AGBL2 to regulate the α-tubulin tyrosination cycle. Cancer research 57 21303978
2013 Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN. Oncogenesis 50 23588494
2007 Promoter hypermethylation of CCNA1, RARRES1, and HRASLS3 in nasopharyngeal carcinoma. Oral oncology 45 17689134
2006 RARRES1 expression is significantly related to tumour differentiation and staging in colorectal adenocarcinoma. European journal of cancer (Oxford, England : 1990) 41 16426842
2018 Tumor suppressor RARRES1- A novel regulator of fatty acid metabolism in epithelial cells. PloS one 27 30557378
2016 Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1. Oncotarget 27 27286452
2017 Multiple roles of RARRES1 in prostate cancer: Autophagy induction and angiogenesis inhibition. PloS one 26 28678839
2010 Tumor Suppressor RARRES1 Regulates DLG2, PP2A, VCP, EB1, and Ankrd26. Journal of Cancer 26 20842219
2009 Role of the RARRES1 gene in nasopharyngeal carcinoma. Cancer genetics and cytogenetics 24 19737656
2024 Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury. Kidney international 22 38697478
2012 Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. PloS one 17 22615834
2022 Interaction of RARRES1 with ICAM1 modulates macrophages to suppress the progression of kidney renal clear cell carcinoma. Frontiers in immunology 10 36353618
2021 Autocrine and paracrine effects of a novel podocyte gene, RARRES1. Kidney international 10 34556297
2019 Tumor suppressor RARRES1 links tubulin deglutamylation to mitochondrial metabolism and cell survival. Oncotarget 10 30899431
2012 Identification of RARRES1 as a core regulator in liver fibrosis. Journal of molecular medicine (Berlin, Germany) 10 22669512
2019 RARRES1 is a novel immune-related biomarker in GBM. American journal of translational research 9 31632537
2012 Secretome survey of human plexiform neurofibroma derived Schwann Cells reveals a secreted form of the RARRES1 protein. International journal of molecular sciences 9 22942771
2024 RARRES1 inhibits hepatocellular carcinoma progression and increases its sensitivity to lenvatinib through interaction with SPINK2. Biology direct 8 38388961
2020 Expression of RARRES1 and AGBL2 and progression of conventional renal cell carcinoma. British journal of cancer 8 32307444
2022 Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice. International journal of biological sciences 6 35541897
2023 Astragalus polysaccharide alleviates angiotensin II-induced glomerular podocyte dysfunction by inhibiting the expression of RARRES1 and LCN2. Clinical and experimental pharmacology & physiology 3 36876579
2026 RARRES1 marks an immune-cold, chemoresistance-associated malignant epithelial subpopulation enriched in pancreatic ductal adenocarcinoma. Cancer immunology, immunotherapy : CII 0 41854891
2026 Multi-omics analysis identifies RARRES1 as a potential biomarker linked to immunosuppressive microenvironment and its radiomics prediction in ovarian cancer. Translational cancer research 0 42180955
2025 RARRES1 attenuates H2O2-induced RPE cell injury and inhibits choroidal neovascularization. Frontiers in physiology 0 41178994
2024 Preventing MMP23-mediated cleavage of podocyte RARRES1: a novel strategy to halt chronic kidney disease progression? Kidney international 0 38906649
2021 Correction: Tumor suppressor RARRES1 links tubulin deglutamylation to mitochondrial metabolism and cell survival. Oncotarget 0 34733422

Missed literature

Know a paper Affinage missed for RARRES1? Flag it for the maintainers and the community.

No submissions yet.