Affinage

CNPY2

Protein canopy homolog 2 · UniProt Q9Y2B0

Length
182 aa
Mass
20.7 kDa
Annotated
2026-06-09
31 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNPY2 is an endoplasmic reticulum luminal and secreted protein that functions as a stress-responsive switch coupling the unfolded protein response to cell fate, migration, and proliferation across multiple tissues (PMID:28869608, PMID:25589425). Within the ER, CNPY2 is held in complex with the chaperone GRP78; upon ER stress it dissociates and directly engages PERK to drive CHOP expression, and CHOP in turn transcriptionally upregulates CNPY2 in a feed-forward loop, with CNPY2 deletion blocking the PERK–CHOP axis and protecting mice from UPR-induced liver damage (PMID:28869608). This same PERK/eIF2α/ATF4/CHOP branch is engaged in disease contexts, where CNPY2 promotes endothelial injury and atherosclerosis (PMID:37103758) and drives ferroptosis with loss of mitochondria-associated ER membrane integrity in renal tubular cells (PMID:40211809). As a secreted factor, CNPY2 is a direct HIF-1α transcriptional target under hypoxia and activates Cdc42/PAK1/FAK signaling to promote smooth muscle cell proliferation, migration, and vascular sprouting (PMID:25589425), and downstream of FGF21 it interacts with the E3 ligase MYLIP/IDOL to stabilize LDLR (PMID:22378787) and blocks MYLIP-UBE2D1-mediated ubiquitination to stabilize the androgen receptor (PMID:29707137). In cancer and other proliferative settings, CNPY2 acts through AKT/GSK3β signaling to promote EMT, glycolysis, and survival (PMID:29569784, PMID:33721832, PMID:38544560) and through NF-κB to confer apoptosis resistance and restrain cellular senescence (PMID:29864955, PMID:42163428).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2012 Medium

    Established CNPY2 as a regulator of lipoprotein receptor levels by placing it in the FGF21–MYLIP/IDOL–LDLR axis, the first functional role assigned to the protein.

    Evidence Overexpression/knockdown in hepatocytes and macrophages with DiI-LDL uptake and LDLR western blot, epistasis with FGF21

    PMID:22378787

    Open questions at the time
    • MYLIP interaction inferred from prior literature, not directly shown by Co-IP here
    • single lab
    • mechanism of how CNPY2 modulates MYLIP activity not resolved
  2. 2015 High

    Defined CNPY2 as a hypoxia-induced secreted angiogenic factor, linking its transcriptional control (HIF-1α) to a downstream Cdc42/PAK1/FAK migratory program.

    Evidence ER/Golgi co-localization, Brefeldin A, ELISA, ChIP and luciferase on the CNPY2 promoter, kinase activation assays, aortic ring and retinal revascularization models

    PMID:25589425

    Open questions at the time
    • receptor mediating secreted CNPY2 signaling not identified
    • how Cdc42/PAK1/FAK is activated by extracellular CNPY2 unknown
  3. 2016 Medium

    Implicated CNPY2 as a negative regulator of the p53 pathway in colorectal cancer, connecting it to tumor growth and apoptosis control.

    Evidence Stable shRNA knockdown in HCT116, xenografts, p53 activity assay, p21/CDK2 westerns, apoptosis assays

    PMID:26835537

    Open questions at the time
    • direct molecular link between CNPY2 and p53 not established
    • single cell-line context
  4. 2017 High

    Resolved the central ER-stress mechanism: CNPY2 dissociates from GRP78 and binds PERK to launch the PERK-CHOP UPR branch, with CHOP feeding back to upregulate CNPY2.

    Evidence Reciprocal Co-IP (CNPY2-GRP78, CNPY2-PERK), CNPY2 knockout mouse with liver damage readout, genetic rescue, CHOP-driven CNPY2 reporter assays

    PMID:28869608

    Open questions at the time
    • structural basis of the CNPY2-PERK interaction not defined
    • what triggers GRP78 release of CNPY2 mechanistically unresolved
  5. 2018 Medium

    Extended CNPY2's MYLIP regulation to the androgen receptor and connected it to AKT/GSK3β-driven EMT and NF-κB-mediated chemoresistance in cancer.

    Evidence Co-IP of MYLIP-UBE2D1 with/without CNPY2 and ubiquitination/rescue assays in prostate cancer; overexpression with AKT and NF-κB inhibitor rescue in NSCLC

    PMID:29569784 PMID:29707137 PMID:29864955

    Open questions at the time
    • whether CNPY2 directly binds MYLIP or UBE2D1 not distinguished
    • AKT and NF-κB effects rest on overexpression plus pharmacological rescue
    • single-lab studies
  6. 2021 Medium

    Generalized CNPY2-AKT signaling to metabolic and neuroprotective outcomes, and confirmed HIF-1α transcriptional control in a second context.

    Evidence ChIP/reporter for HIF-1α on CNPY2 promoter plus glycolysis assays in cervical cancer; CNPY2 overexpression with AKT inhibitor rescue in MPP+/MPTP Parkinson's models

    PMID:33721832 PMID:34060992

    Open questions at the time
    • mechanism linking CNPY2 to AKT activation not defined
    • tissue-context dependence of pro- vs anti-apoptotic roles unexplained
  7. 2024 Medium

    Showed context-dependent UPR outcomes — CNPY2 protects neurons by dampening ATF6/CHOP yet drives VSMC phenotype switching via Akt/mTOR/GSK-3β.

    Evidence Gain/loss-of-function with recombinant protein in neurons (ATF6/CHOP readouts); shRNA knockdown with SC79 Akt rescue in PDGF-BB-stimulated VSMCs

    PMID:38544560 PMID:39359687

    Open questions at the time
    • why CNPY2 reduces CHOP in neurons but induces it elsewhere is unexplained
    • single-lab studies
  8. 2025 Medium

    Linked CNPY2-PERK/ATF4/CHAC1 signaling to ferroptosis and MAM disruption in diabetic kidney injury, broadening its UPR-coupled pathology roles.

    Evidence Knockdown and overexpression in renal tubular epithelial cells and db/db mice, PERK/ATF4/CHAC1 westerns, ferroptosis markers, MAM integrity assessment

    PMID:40211809

    Open questions at the time
    • how CNPY2 controls MAM integrity mechanistically unknown
    • single lab
  9. 2026 Medium

    Defined upstream epigenetic control of CNPY2 (CBX6/TRIM26) and its NF-κB-IL-8-neutrophil output in bladder cancer.

    Evidence Co-IP (TRIM26-CBX6), ChIP for H2AK119ub1 at the CNPY2 promoter, NF-κB reporter, IL-8 ELISA, neutrophil recruitment and in vivo tumor model

    PMID:42163428

    Open questions at the time
    • direct CNPY2-to-NF-κB molecular link not shown
    • single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The receptor and biochemical mechanism by which secreted CNPY2 transduces signals into AKT, NF-κB, and Cdc42 pathways, and the structural basis of its GRP78/PERK and MYLIP interactions, remain unresolved.
  • no cell-surface receptor for secreted CNPY2 identified
  • no structural model of CNPY2 complexes
  • context-dependent pro- vs anti-survival switch mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005576 extracellular region 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-392499 Metabolism of proteins 2
Partners
EIF2AK3HSPA5MYLIPUBE2D1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 CNPY2 is an ER luminal protein that is released from GRP78 upon ER stress; free CNPY2 then directly engages PERK to induce CHOP expression, initiating the UPR. Deletion of CNPY2 blocked the PERK-CHOP pathway and protected mice from UPR-induced liver damage. CHOP transcriptionally upregulates CNPY2 in a forward-feed loop. Co-immunoprecipitation (CNPY2-GRP78 and CNPY2-PERK interactions), CNPY2 knockout mouse model with liver damage readout, genetic rescue, reporter assays for CHOP-driven CNPY2 transcription Nature structural & molecular biology High 28869608
2015 CNPY2 protein co-localizes with the endoplasmic reticulum and Golgi; Brefeldin A treatment causes CNPY2 accumulation in the ER. CNPY2 is a secreted protein detectable in blood of mice and humans and in conditioned medium of cultured SMCs. HIF-1α directly binds a hypoxia response element (HRE-1157) upstream of the CNPY2 promoter to transcriptionally upregulate CNPY2 under hypoxia. Secreted CNPY2 activates Cdc42, PAK1, and FAK in SMCs, promoting proliferation and migration in vitro and aortic ring sprouting ex vivo. Immunofluorescence/co-localization with ER/Golgi markers, Brefeldin A treatment, ELISA for secreted protein, chromatin immunoprecipitation (ChIP), luciferase reporter assay, HIF-1α siRNA knockdown, kinase activation assays (Cdc42/PAK1/FAK), aortic ring sprouting assay, mouse retinal revascularization model Cardiovascular research High 25589425
2012 CNPY2 (Cnpy2/Msap) interacts with the E3 ubiquitin ligase Mylip/Idol. Overexpression of CNPY2 increases LDLR levels, and knockdown of CNPY2 abolishes the FGF21-induced increase in LDLR, placing CNPY2 downstream of FGF21 and upstream of LDLR regulation via Mylip/Idol. Overexpression and siRNA knockdown in human hepatocyte cells and mouse macrophages, DiI-LDL uptake assay, western blot for LDLR levels, epistasis by knockdown rescue The Journal of biological chemistry Medium 22378787
2018 CNPY2 inhibits MYLIP-mediated AR ubiquitination in prostate cancer cells by blocking the interaction between MYLIP and its cognate E2 ubiquitin ligase UBE2D1, thereby stabilizing AR protein and upregulating AR target genes (e.g., KLK3/PSA). Cell growth inhibition by CNPY2 knockdown was rescued by AR overexpression, placing CNPY2 upstream of AR stability. Co-immunoprecipitation (MYLIP-UBE2D1 interaction assay with CNPY2 present/absent), ubiquitination assay, CNPY2 knockdown, AR overexpression rescue, gene expression analysis Oncotarget Medium 29707137
2018 Overexpression of CNPY2 in NSCLC cells activates the AKT/GSK3β pathway, leading to inactivation of GSK-3β, increased Snail levels, decreased E-cadherin, and promotion of epithelial-mesenchymal transition (EMT). AKT inhibition suppresses CNPY2-induced malignant transformation. CNPY2 overexpression in NSCLC cell lines, wound healing and Transwell invasion assays, western blot for AKT/GSK3β/Snail/E-cadherin, AKT inhibitor treatment Cell biology international Medium 29569784
2016 CNPY2 knockdown in HCT116 colorectal cancer cells reversibly increases p53 activity, which upregulates p21 and reduces CDK2, inhibiting tumor growth and inducing apoptosis. CNPY2 thus negatively regulates the p53 pathway in colorectal cancer cells. Stable shRNA knockdown of CNPY2 in HCT116 cells, xenograft tumor model in nude mice, p53 activity assay, western blot for p21 and CDK2, apoptosis assays The American journal of pathology Medium 26835537
2018 CNPY2 overexpression in NSCLC cells inhibits cisplatin-induced apoptosis through hyperactivation of the NF-κB signaling pathway; blocking NF-κB re-sensitizes CNPY2-overexpressing cells to apoptosis. CNPY2 overexpression in NSCLC cells, colony formation, Annexin V, and TUNEL apoptosis assays, NF-κB pathway inhibitor treatment, western blot Biomedicine & pharmacotherapy Medium 29864955
2025 CNPY2 activates the PERK/ATF4/CHAC1 signaling pathway to facilitate ferroptosis in renal tubular epithelial cells, disrupting mitochondria-associated ER membrane (MAM) integrity. Downregulation of CNPY2 alleviates ferroptosis and improves MAM integrity in db/db mice, while overexpression aggravates tubular injury. CNPY2 knockdown and overexpression in renal tubular epithelial cells and db/db mouse model, western blot for PERK/ATF4/CHAC1 pathway, ferroptosis markers, MAM integrity assessment Advanced science Medium 40211809
2017 CNPY2 promotes growth of renal cell carcinoma cells and upregulates TP53 gene expression; CDKN1A (p21) is upregulated by both p53 and CNPY2, suggesting CNPY2 drives RCC cell growth via upregulation of TP53. CNPY2 overexpression/knockdown in RCC cell lines, gene expression analysis (TP53, CDKN1A), cell growth assays Biochemical and biophysical research communications Low 28235487
2019 In hypoxia/reoxygenation-injured HUVECs, liraglutide increases CNPY2-PERK pathway protein expression (CNPY2, GRP78, PERK, ATF4) and upregulates HIF-1α and VEGF. The PERK inhibitor GSK2606414 abrogates ATF4, HIF-1α, and VEGF upregulation, placing CNPY2-PERK upstream of VEGF expression. H/R injury model in HUVECs, western blot and RT-PCR for pathway proteins, PERK inhibitor GSK2606414 treatment, ELISA for HIF-1α and VEGF, tube formation assay Frontiers in pharmacology Low 31396081
2021 In cervical cancer cells, HIF-1α transcriptionally upregulates CNPY2 (confirmed by dual-luciferase reporter and ChIP). CNPY2 promotes glycolysis (glucose consumption, lactate production, ATP production) via activation of the AKT pathway; knockdown of CNPY2 inhibits these metabolic effects. Dual-luciferase reporter assay, chromatin immunoprecipitation (HIF-1α on CNPY2 promoter), siRNA knockdown and overexpression of CNPY2, metabolic assays (glucose, lactate, ATP), western blot for AKT pathway Biochemical and biophysical research communications Medium 33721832
2021 In a Parkinson's disease model, CNPY2 overexpression activates the AKT/GSK3β signaling pathway, reducing MPP+-induced neuronal apoptosis, ROS accumulation, and mitochondrial dysfunction; these protective effects were blocked by the AKT inhibitor MK-2206 2HCl. Overexpression of CNPY2 in MPP+-treated SH-SY5Y cells and MPTP mouse model, western blot for AKT/GSK3β/Bcl-2/Bax/caspase-3, flow cytometry for ROS and mitochondrial membrane potential, MTT and TUNEL assays, AKT inhibitor treatment Current neurovascular research Medium 34060992
2024 CNPY2 overexpression protects neuronal cells against tunicamycin-induced ER stress, enhancing viability, while CNPY2 downregulation reduces viability. Recombinant CNPY2 increased cortical neuron survival after ER stress. CNPY2 reduces the ATF6 branch of ER stress and decreases CHOP expression. CNPY2 overexpression and shRNA knockdown in neuroblastoma cells, recombinant CNPY2 treatment of cortical neurons, tunicamycin-induced ER stress, cell viability assay, western blot/immunostaining for ATF6 and CHOP Frontiers in molecular neuroscience Medium 39359687
2024 CNPY2 knockdown in PDGF-BB-stimulated vascular smooth muscle cells inhibits hyperproliferation, migration, and phenotypic transformation by suppressing activation of the Akt/mTOR/GSK-3β pathway; reactivation of Akt with SC79 reverses these inhibitory effects, placing CNPY2 upstream of Akt/mTOR/GSK-3β in VSMC phenotype switching. shRNA knockdown of CNPY2 in PDGF-BB-stimulated VSMCs, Akt activator SC79 rescue, western blot for p-Akt/p-mTOR/p-GSK-3β, proliferation, migration and phenotypic transformation assays Experimental and therapeutic medicine Medium 38544560
2023 Exogenous CNPY2 aggravates ox-LDL-induced endothelial cell activation, inflammation, and apoptosis via the PERK/eIF2α/CHOP signaling pathway; the PERK inhibitor GSK2606414 blocks CNPY2-induced MAEC injury. In vivo, CNPY2 promotes atherosclerosis in ApoE-/- mice through PERK signaling. Exogenous CNPY2 treatment of mouse aortic endothelial cells (MAECs), PERK inhibitor GSK2606414, western blot for PERK/eIF2α/CHOP, ApoE-/- mouse atherosclerosis model with CNPY2 modulation Journal of molecular histology Medium 37103758
2024 CNPY2 deficiency in tendon stem/progenitor cells (TSPCs) causes cellular senescence and development of the senescence-associated secretory phenotype (SASP). NF-κB signaling is activated in CNPY2-knockdown TSPCs, and pharmacological NF-κB inhibition with BMS-345541 attenuates SASP, indicating CNPY2 suppresses SASP via restraint of the NF-κB pathway. CNPY2 knockdown in TSPCs, NF-κB inhibitor BMS-345541 treatment, SASP marker measurement, senescence assays Tissue & cell Low 39755057
2026 In bladder cancer, CBX6 transcriptionally represses CNPY2 by catalyzing H2AK119ub1 deposition on the CNPY2 promoter. TRIM26-mediated ubiquitination and degradation of CBX6 leads to CNPY2 upregulation, which activates NF-κB and stimulates IL-8 secretion to recruit neutrophils and induce NET formation. Co-immunoprecipitation (TRIM26-CBX6 binding), ubiquitination assay, ChIP for H2AK119ub1 at CNPY2 promoter, CBX6 degradation assay, NF-κB reporter, IL-8 ELISA, neutrophil recruitment assay, in vivo tumor model with DNase I Drug development research Medium 42163428
2019 miR-30a-3p directly downregulates CNPY2 in lung adenocarcinoma cells; overexpression of miR-30a-3p inhibited cancer cell proliferation, invasion, migration, and EMT via CNPY2 suppression, validated by dual-luciferase reporter assay confirming CNPY2 as a direct miR-30a-3p target. Dual-luciferase reporter assay confirming miR-30a-3p targeting of CNPY2 3'UTR, miR-30a-3p overexpression in EKVX cells, western blot for CNPY2, proliferation/migration/invasion assays, EMT marker analysis Oncology reports Medium 31894275

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Fibroblast growth factor-21 (FGF21) regulates low-density lipoprotein receptor (LDLR) levels in cells via the E3-ubiquitin ligase Mylip/Idol and the Canopy2 (Cnpy2)/Mylip-interacting saposin-like protein (Msap). The Journal of biological chemistry 62 22378787
2017 CNPY2 is a key initiator of the PERK-CHOP pathway of the unfolded protein response. Nature structural & molecular biology 55 28869608
2021 Berberine Attenuates Cerebral Ischemia-Reperfusion Injury Induced Neuronal Apoptosis by Down-Regulating the CNPY2 Signaling Pathway. Frontiers in pharmacology 47 33995012
2015 A secreted protein (Canopy 2, CNPY2) enhances angiogenesis and promotes smooth muscle cell migration and proliferation. Cardiovascular research 40 25589425
2016 Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway. The American journal of pathology 33 26835537
2019 Dexmedetomidine attenuates neuronal injury after spinal cord ischaemia-reperfusion injury by targeting the CNPY2-endoplasmic reticulum stress signalling. Journal of cellular and molecular medicine 31 31625681
2025 CNPY2 Aggravates Renal Tubular Cell Ferroptosis in Diabetic Nephropathy by Regulating PERK/ATF4/CHAC1 Pathway and MAM Integrity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 40211809
2019 Liraglutide Increases VEGF Expression via CNPY2-PERK Pathway Induced by Hypoxia/Reoxygenation Injury. Frontiers in pharmacology 27 31396081
2019 miR‑30a‑3p suppresses the proliferation and migration of lung adenocarcinoma cells by downregulating CNPY2. Oncology reports 27 31894275
2014 Expression of CNPY2 in mouse tissues: quantification and localization. PloS one 26 25393402
2019 Protective effect of Barbaloin in a rat model of myocardial ischemia reperfusion injury through the regulation of the CNPY2‑PERK pathway. International journal of molecular medicine 23 30864682
2018 The CNPY2 enhances epithelial-mesenchymal transition via activating the AKT/GSK3β pathway in non-small cell lung cancer. Cell biology international 22 29569784
2017 CNPY2 promoted the proliferation of renal cell carcinoma cells and increased the expression of TP53. Biochemical and biophysical research communications 21 28235487
2018 CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells. Oncotarget 19 29707137
2021 Hypoxia-induced CNPY2 upregulation promotes glycolysis in cervical cancer through activation of AKT pathway. Biochemical and biophysical research communications 16 33721832
2021 Sleeping Beauty insertional mutagenesis screen identifies the pro-metastatic roles of CNPY2 and ACTN2 in hepatocellular carcinoma tumor progression. Biochemical and biophysical research communications 15 33482578
2022 Angiotensin-(1-9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway. Apoptosis : an international journal on programmed cell death 13 36422742
2021 LncRNA LINC00342 promotes gastric cancer progression by targeting the miR-545-5p/CNPY2 axis. BMC cancer 13 34715819
2018 Serum CNPY2 isoform 2 represents a novel biomarker for early detection of colorectal cancer. Aging 12 30070972
2018 CNPY2 enhances resistance to apoptosis induced by cisplatin via activation of NF-κB pathway in human non-small cell lung cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 11 29864955
2024 Progress in Research on CNPY2 in Diseases. Mini reviews in medicinal chemistry 7 37259932
2024 CNPY2 governs PDGF‑BB‑treated vascular smooth muscle cell proliferation, migration and phenotypic transformation via the Akt/mTOR/GSK‑3β signaling pathway. Experimental and therapeutic medicine 7 38544560
2021 Canopy Fibroblast Growth Factor Signaling Regulator 2 (CNPY2) Inhibits Neuron Apoptosis in Parkinson's Disease via the AKT/GSK3β Pathway. Current neurovascular research 6 34060992
2024 CNPY2 protects against ER stress and is expressed by corticostriatal neurons together with CTIP2 in a mouse model of Huntington's disease. Frontiers in molecular neuroscience 5 39359687
2023 The role of CNPY2 in endothelial injury and inflammation during the progress of atherosclerosis. Journal of molecular histology 4 37103758
2025 CNPY2 in Solid Tumors: Mechanisms, Biomarker Potential, and Therapeutic Implications. Biology 2 40001982
2025 LncRNA ZFAS1 Combined with SRSF1 Regulate CNPY2 Expression and Leads to Microglia Endoplasmic Reticulum Stress-Induced Spinal Cord Injury. Molecular neurobiology 1 40465066
2024 CNPY2 modulates senescence-associated secretory phenotype in tendon stem/progenitor cells. Tissue & cell 1 39755057
2022 [Effects of aerobic exercise on CNPY2-PERK pathway in the liver of mice with non-alcoholic fatty liver disease]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 1 36062783
2026 Multifaceted role of CNPY2 beyond ER stress: Disease implications and therapeutic potential. Cell stress 0 42016348
2026 TRIM26-Mediated CBX6 Ubiquitination Triggers NETosis to Drive Bladder Cancer Tumor Growth via the CNPY2/NF-κB Signaling Pathway. Drug development research 0 42163428

Missed literature

Know a paper Affinage missed for CNPY2? Flag it for the maintainers and the community.

No submissions yet.