Affinage

RCN1

Reticulocalbin-1 · UniProt Q15293

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RCN1 (reticulocalbin 1) is an ER-resident EF-hand calcium-binding protein that acts as a negative regulator of ER stress signaling and ER-mitochondria calcium coupling (PMID:28319095, PMID:41385809). Its first two EF-hand motifs bind the luminal domain of IP3R1 to inhibit ER calcium release, and this calcium-sensing interaction also suppresses IP3R1-GRP75 association and ER-to-mitochondria calcium transfer; loss of RCN1 strengthens ER-mitochondria coupling (PMID:28319095, PMID:41385809). Through dampening of the UPR, RCN1 limits PERK-CHOP signaling and thereby inhibits ER stress-induced apoptosis, a protective role demonstrated in cancer and in endothelial cells under glycolipotoxic stress (PMID:28319095, PMID:40853392). In drug-resistant and tumor contexts RCN1 engages additional UPR machinery: its EFh1/2 domain binds GRP78 to promote GRP78 dissociation from IRE1α and sustain IRE1α-XBP1s-c-MYC signaling, and it interacts with XBP1 to drive ER stress in keloid fibroblasts (PMID:34663798, PMID:40214031). RCN1 functions as a negative modulator of B-RAF/MEK signaling in cardiomyocytes and, conversely, supports PI3K-AKT(-mTOR) signaling to promote tumor cell proliferation, migration, and invasion, in part through binding KIF14 (PMID:24492844, PMID:40927771). RCN1 protein abundance is controlled by TRIM11-mediated ubiquitination, while its mRNA is regulated by ALKBH5/m6A-YTHDF2-dependent decay and by miR-26b targeting of its 3'-UTR (PMID:41385809, PMID:40214031, PMID:40688319).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2014 Medium

    Established RCN1 as a signaling modulator rather than a purely structural ER protein by placing it as a negative regulator of the B-RAF/MEK cascade.

    Evidence cDNA expression screen with B-RAF luciferase reporter plus gain- and loss-of-function in neonatal rat cardiomyocytes measuring MEK1/2 phosphorylation and hypertrophy

    PMID:24492844

    Open questions at the time
    • No direct binding partner in the B-RAF pathway identified
    • Mechanism linking ER calcium binding to MEK regulation not resolved
  2. 2017 High

    Defined the core molecular mechanism: RCN1 binds IP3R1 via its first two EF-hands to suppress ER calcium release and the PERK-CHOP arm of the UPR, protecting against ER stress-induced apoptosis.

    Evidence Reciprocal Co-IP with EF-hand mutagenesis mapping the IP3R1 luminal loop 3 interaction, plus calcium-release, UPR, and apoptosis assays under NF-κB-driven ER stress

    PMID:28319095

    Open questions at the time
    • Structural basis of EF-hand/IP3R1 recognition not solved
    • Whether calcium occupancy of the EF-hands gates the interaction not directly tested in this study
  3. 2021 Medium

    Extended RCN1's UPR role to the IRE1α arm, showing it can promote pro-survival IRE1α-XBP1s-c-MYC signaling in a drug-resistance context.

    Evidence Co-IP mapping RCN1-GRP78 interaction to the EFh1/2 domain plus overexpression/knockdown with pathway readouts in sorafenib-resistant HCC cells

    PMID:34663798

    Open questions at the time
    • Single lab, no reciprocal validation of GRP78 dissociation in vitro
    • How RCN1 reconciles UPR suppression (PERK-CHOP) with UPR activation (IRE1α) is unresolved
  4. 2023 Medium

    Linked RCN1 to control of innate immune/cell-death programs, showing its loss triggers IFN-1 and caspase-1/GSDMD pyroptosis.

    Evidence shRNA knockdown and Rcn1 deletion in AML cells with caspase-1/GSDMD and IFN-1 readouts plus NSG xenografts

    PMID:37746742

    Open questions at the time
    • Molecular connection from ER calcium/UPR role to pyroptosis not defined
    • No direct partner mediating IFN-1 induction identified
  5. 2025 Medium

    Connected RCN1 abundance to upstream regulation by TRIM11 ubiquitination and to ER-mitochondria calcium crosstalk via the IP3R1-GRP75 axis.

    Evidence Co-IP, proteomics, and calcium-transfer assays in HCC xenograft and spontaneous models

    PMID:41385809

    Open questions at the time
    • TRIM11 ubiquitination site on RCN1 not mapped
    • Quantitative contribution of ER-mito coupling to drug resistance not isolated
  6. 2025 Medium

    Defined mRNA-level control of RCN1 by m6A (ALKBH5/YTHDF2) and miR-26b, and added downstream effectors KIF14/PI3K-AKT and XBP1 across multiple tumor and fibrosis contexts.

    Evidence MeRIP and Co-IP in keloid fibroblasts (XBP1), IP-MS plus xenografts in cervical cancer (KIF14/PI3K-AKT-mTOR), luciferase 3'-UTR reporter in NSCLC (miR-26b), and PI3K/AKT rescue in DLBCL

    PMID:40214031 PMID:40659094 PMID:40688319 PMID:40927771

    Open questions at the time
    • DLBCL epistasis rests on pharmacological rescue without direct binding data
    • Whether KIF14 binding and PI3K-AKT activation are mechanistically coupled not established
    • Tissue specificity of m6A vs miR-26b control not compared

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RCN1's single calcium-sensing/EF-hand activity is mechanistically partitioned between opposing outputs (PERK-CHOP suppression versus IRE1α-XBP1s activation; B-RAF/MEK inhibition versus PI3K-AKT promotion) across cell types.
  • No structural model of RCN1 in any complex
  • No unified framework reconciling pro-survival and pro-death roles
  • Calcium-dependence of partner switching not directly measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140097 catalytic activity, acting on DNA 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
GRP75GRP78IP3R1KIF14TRIM11XBP1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 RCN1 (reticulocalbin 1) is transactivated by NF-κB during ER stress. The first two EF-hand calcium-binding motifs of RCN1 specifically interact with IP3R1 on loop 3 of its ER luminal domain, inhibiting ER calcium release and suppressing PERK-CHOP signaling, thereby inhibiting ER stress-induced apoptosis. Co-immunoprecipitation (Co-IP) identifying RCN1-IP3R1 interaction; EF-hand domain mutagenesis; depletion/overexpression assays measuring UPR activation, calcium release, and apoptosis Oncogenesis High 28319095
2021 RCN1 promotes dissociation of GRP78 from IRE1α in sorafenib-resistant HCC cells by interacting with GRP78 through its EFh1/2 domain, leading to sustained activation of the IRE1α-XBP1s pathway and downstream c-MYC signaling. Co-immunoprecipitation identifying RCN1-GRP78 interaction via EFh1/2 domain; overexpression/knockdown in sorafenib-resistant HCC cells with pathway activity readouts Cell death discovery Medium 34663798
2025 RCN1 uses its EF-hand (EFh1/2) domains to sense ER calcium concentration and modulates its binding to IP3R1 accordingly, suppressing IP3R1-GRP75 interaction and ER-to-mitochondria calcium transfer. Downregulation of RCN1 strengthens ER-mitochondria coupling. TRIM11-mediated ubiquitination regulates RCN1 protein stability. Co-IP; overexpression/knockdown in HCC xenograft and spontaneous models; proteomic analysis; functional assays for ER-mitochondria calcium transfer Drug resistance updates Medium 41385809
2014 RCN1 functions as a negative modulator of B-RAF activity in cardiomyocytes, inhibiting phenylephrine-induced hypertrophy and reducing MEK1/2 phosphorylation. Conversely, adenoviral knockdown of RCN1 induced cardiomyocyte hypertrophy and increased MEK1/2 phosphorylation. Eukaryotic cDNA expression screen with dual-luciferase B-RAF reporter assay; adenovirus-mediated overexpression and miRNA-mediated knockdown of RCN1; measurement of MEK1/2 phosphorylation and hypertrophic markers in neonatal rat cardiomyocytes Cardiovascular research Medium 24492844
2025 RCN1 binds KIF14 (identified by immunoprecipitation-mass spectrometry), and this interaction promotes activation of the PI3K-AKT-mTOR pathway, facilitating proliferation, migration, and invasion of cervical cancer cells. Immunoprecipitation tandem mass spectrometry (IP-MS) identifying KIF14 as RCN1 binding partner; knockdown and overexpression assays; Western blotting for PI3K-AKT-mTOR pathway; mouse xenograft model International journal of general medicine Medium 40927771
2025 ALKBH5 demethylase upregulates RCN1 expression by reducing m6A-YTHDF2-mediated degradation of RCN1 mRNA. Overexpression of RCN1 upregulates XBP1, GRP78, and IRE1α protein levels and promotes ER stress in keloid fibroblasts; RCN1 interacts with XBP1 as shown by Co-IP. Knockdown of RCN1 inhibited keloid formation in a mouse model. Methylated RNA immunoprecipitation (MeRIP) assessing m6A modification of RCN1 mRNA; co-immunoprecipitation confirming RCN1-XBP1 interaction; overexpression/knockdown with Western blot for ER stress markers; TEM for ER structure; in vivo mouse keloid model Journal of cosmetic dermatology Medium 40214031
2025 RCN1 knockdown in DLBCL cells suppresses activation of the PI3K/AKT signaling pathway, and reactivation of PI3K/AKT with agonist 740Y-P offsets the anti-tumor effect of RCN1 knockdown, placing RCN1 upstream of PI3K/AKT in DLBCL malignancy and macrophage M2 polarization. Genetic knockdown with pathway rescue by PI3K/AKT agonist; Western blotting for PI3K/AKT markers; flow cytometry for macrophage polarization markers Molecular and cellular probes Low 40659094
2025 TRIM11-mediated ubiquitination regulates RCN1 protein stability in endothelial cells under glycolipotoxicity conditions; RCN1 overexpression alleviates ER stress (reducing PERK phosphorylation and CHOP expression) and promotes angiogenesis, while RCN1 silencing intensifies PERK-CHOP signaling and impairs endothelial function. Proteomic analysis; overexpression and siRNA-mediated silencing; Western blotting for PERK phosphorylation and CHOP; RNA sequencing; in vivo diabetic mouse ulcer healing model Cellular and molecular life sciences Medium 40853392
2023 RCN1 knockdown in AML cells upregulates type I interferon (IFN-1) expression and promotes pyroptosis through caspase-1 and gasdermin D (GSDMD) signaling. RCN1 suppression also inhibited tumor growth in NSG mouse xenograft models. shRNA-mediated RCN1 knockdown; flow cytometry and Western blotting for caspase-1 and GSDMD; IFN-1 measurement; NSG mouse xenograft model; Rcn1 gene deletion in mouse AML cell lines Molecular oncology Medium 37746742
2025 miR-26b directly binds to the 3'-UTR of RCN1 mRNA and suppresses RCN1 expression, placing RCN1 downstream of miR-26b in NSCLC cell proliferation, invasion, and migration. miR-26b expression is downregulated by DNA hypermethylation in NSCLC. Luciferase reporter assay confirming direct miR-26b binding to RCN1 3'-UTR; methylation-specific PCR; Western blotting; functional cell assays (MTT, transwell) Journal of thoracic disease Medium 40688319

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Overexpression of RCN1 and RCN2, rice TERMINAL FLOWER 1/CENTRORADIALIS homologs, confers delay of phase transition and altered panicle morphology in rice. The Plant journal : for cell and molecular biology 219 12148532
1999 The RCN1-encoded A subunit of protein phosphatase 2A increases phosphatase activity in vivo. The Plant journal : for cell and molecular biology 79 10607292
2007 Specificity of RCN1-mediated protein phosphatase 2A regulation in meristem organization and stress response in roots. Plant physiology 73 18162590
2008 Roles of RCN1, regulatory A subunit of protein phosphatase 2A, in methyl jasmonate signaling and signal crosstalk between methyl jasmonate and abscisic acid. Plant & cell physiology 66 18650210
2017 RCN1 suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling. Oncogenesis 59 28319095
2007 The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. Proceedings of the National Academy of Sciences of the United States of America 49 17954914
2003 The Caenorhabditis elegans homologue of Down syndrome critical region 1, RCN-1, inhibits multiple functions of the phosphatase calcineurin. Journal of molecular biology 40 12684004
2015 Rice Stomatal Closure Requires Guard Cell Plasma Membrane ATP-Binding Cassette Transporter RCN1/OsABCG5. Molecular plant 39 26708605
2006 RCN1-regulated phosphatase activity and EIN2 modulate hypocotyl gravitropism by a mechanism that does not require ethylene signaling. Plant physiology 38 16798939
2012 Exposure to benzo[a]pyrene of Hepatic Cytochrome P450 Reductase Null (HRN) and P450 Reductase Conditional Null (RCN) mice: Detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and 32P-postlabelling. Toxicology letters 33 22759596
2021 RCN1 induces sorafenib resistance and malignancy in hepatocellular carcinoma by activating c-MYC signaling via the IRE1α-XBP1s pathway. Cell death discovery 32 34663798
2020 Salivary NUS1 and RCN1 Levels as Biomarkers for Oral Squamous Cell Carcinoma Diagnosis. In vivo (Athens, Greece) 22 32871760
2013 Mechanistic Evaluation of the Ni(IPr)2-Catalyzed Cycloaddition of Alkynes and Nitriles to Afford Pyridines: Evidence for the Formation of a Key η1-Ni(IPr)2(RCN) Intermediate. Organometallics 20 25214702
2011 Identification of RCN1 and RSA3 as ethanol-tolerant genes in Saccharomyces cerevisiae using a high copy barcoded library. FEMS yeast research 20 22093065
2014 B-RAF and its novel negative regulator reticulocalbin 1 (RCN1) modulates cardiomyocyte hypertrophy. Cardiovascular research 18 24492844
2007 Genetic interaction between 2 tillering genes, reduced culm number 1 (rcn1) and tillering dwarf gene d3, in rice. The Journal of heredity 14 17237471
2023 RCN1 deficiency inhibits oral squamous cell carcinoma progression and THP-1 macrophage M2 polarization. Scientific reports 13 38057406
1976 Enhancement of rIn:rCn-induced interferon production by amphotericin B. Antimicrobial agents and chemotherapy 11 1259412
2023 An Experimental and Master Equation Investigation of Kinetics of the CH2OO + RCN Reactions (R = H, CH3, C2H5) and Their Atmospheric Relevance. The journal of physical chemistry. A 9 36602183
2014 Rice RCN1/OsABCG5 mutation alters accumulation of essential and nonessential minerals and causes a high Na/K ratio, resulting in a salt-sensitive phenotype. Plant science : an international journal of experimental plant biology 9 24908511
2023 Downregulation of RCN1 promotes pyroptosis in acute myeloid leukemia cells. Molecular oncology 7 37746742
2024 Downregulation of RCN1 inhibits esophageal squamous cell carcinoma progression and M2 macrophage polarization. PloS one 6 38713738
2012 Immunomodulatory response of mice splenocytes induced by RcaL, a lectin isolated from cobia fish (Rachycentron canadum) serum. Applied biochemistry and biotechnology 4 22941310
2025 ALKBH5 Inhibits YTHDF2-m6A-Mediated Degradation of RCN1 mRNA to Promote Keloid Formation by Activating IRE1α-XBP1-Mediated ER Stress. Journal of cosmetic dermatology 2 40214031
2025 GPX1 and RCN1 as New Endoplasmic Reticulum Stress-Related Biomarkers in Multiple Sclerosis Brain Tissue and Their Involvement in the APP-CD74 Pathway: An Integrated Study Combining Machine Learning and Multi-Omics. International journal of molecular sciences 2 40650067
2013 The rice REDUCED CULM NUMBER11 gene controls vegetative growth under low-temperature conditions in paddy fields independent of RCN1/OsABCG5. Plant science : an international journal of experimental plant biology 2 23987813
2025 RCN1 affects malignant progression and macrophage M2 polarization in diffuse large B-cell lymphoma. Molecular and cellular probes 1 40659094
2025 RCN1 Binds KIF14 and Promotes the Malignant Growth of Cervical Cancer Through the PI3K-AKT Pathway. International journal of general medicine 1 40927771
2025 Hyperbaric oxygen targets RCN1 to modulate ER-mitochondria crosstalk and ameliorate sorafenib resistance in hepatocellular carcinoma. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 1 41385809
2024 Biochemical analyses reveal new insights into RCAN1/Rcn1 inhibition of calcineurin. The FEBS journal 1 39241105
1996 Replication of rat coronaviruses in intestinal cell line, RCN-9, derived from F344 rats. Experimental animals 1 8902504
2026 RCN1 helps to alleviate the damage of drought stress to rice young spike differentiation. BMC plant biology 0 41968321
2025 Role of miR-26b in regulating non-small cell lung cancer progression via targeting RCN1. Journal of thoracic disease 0 40688319
2025 RCN1 downregulation-driven endoplasmic reticulum stress impairs endothelial function and diabetic foot ulcer healing. Cellular and molecular life sciences : CMLS 0 40853392
2024 Rcn1, the fission yeast homolog of human DSCR1, regulates arsenite tolerance independently from calcineurin. Genes to cells : devoted to molecular & cellular mechanisms 0 38715219
2023 Expression of concern: A cascade process for directly converting nitriles (RCN) to cyanamides (RNHCN) via SO2F2-activated Tiemann rearrangement. Organic & biomolecular chemistry 0 37823257

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