Affinage

CREG1

Protein CREG1 · UniProt O75629

Length
220 aa
Mass
24.1 kDa
Annotated
2026-06-09
71 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CREG1 is a secreted and endolysosomal glycoprotein that restrains cell proliferation and promotes differentiation across multiple lineages (PMID:10815803, PMID:18267954). Its canonical extracellular activity proceeds through direct binding to the mannose-6-phosphate/IGF2 receptor (M6P/IGF2R), engaging receptor domains 7–10 in a glycosylation-dependent manner and domains 11–13 independently of glycosylation; receptor binding is required for CREG1-induced G1/S cell-cycle delay and growth inhibition (PMID:12934103, PMID:21195083). Structurally, CREG1 forms a tight homodimer with an FMN-binding split-barrel fold in which the cofactor pocket is sterically blocked, and a loop mutant that retains dimerization and receptor binding yet loses growth suppression shows that M6P/IGF2R engagement is necessary but not sufficient for its anti-proliferative effect (PMID:16344469). Through M6P/IGF2R-dependent endocytosis CREG1 controls IGF-II trafficking and downstream PI3K/Akt signaling, governing smooth muscle quiescence and migration (PMID:19769965), and the same receptor couples CREG1 to AMPK activation and glucose uptake in skeletal muscle (PMID:36528955). A major function of CREG1 is in the endosomal-lysosomal system, where it localizes and promotes endocytosis, lysosomal acidification, lysosomal biogenesis, and autophagic and mitophagic flux (PMID:33966596, PMID:33726618); in cardiomyocytes it sustains autophagy and is cardioprotective, acting in part through Rab7, the FBXO27-LAMP2 axis, and interaction with HSPD1 in mitochondria (PMID:25774384, PMID:27840305, PMID:37658156, PMID:33726618). CREG1 additionally acts through direct protein interactions to shape signaling: it binds and inhibits ASK1 (blocking MKK4/7-JNK1) and TAK1 to protect hepatocytes (PMID:28508477, PMID:30076625), binds the exocyst component Sec8 to drive cardiomyocyte junction assembly and differentiation (PMID:27334848), and binds MEK1/2 to promote megakaryocyte thrombopoiesis (PMID:37496998). It directs differentiation programs via TGF-β/Smad2 signaling in smooth muscle and erythropoiesis (PMID:35349881, PMID:38953462) and regulates cardiomyocyte ferroptosis through an FBXW7-FOXO1-PDK4 axis (PMID:39094399). CREG1 expression is controlled transcriptionally by GATA1 and is epigenetically silenced by DNMT3B-mediated promoter hypermethylation (PMID:27139506, PMID:32067910).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 Medium

    Established CREG1 as a secreted factor acting in an extracellular differentiation cascade, framing it as a signaling protein rather than a purely intracellular one.

    Evidence Overexpression and conditioned-media rescue in NTERA-2 embryonal carcinoma cells

    PMID:10815803

    Open questions at the time
    • No receptor or molecular mechanism identified
    • Single cell model, gain-of-function only
  2. 2003 High

    Identified M6P/IGF2R as the functional receptor for CREG1, answering how a secreted protein transduces growth arrest.

    Evidence Direct binding assay plus cell-cycle analysis in M6P/IGF2R-deficient cells

    PMID:12934103

    Open questions at the time
    • Downstream signaling from the receptor not defined
    • Glycosylation requirement not yet dissected
  3. 2005 High

    Resolved the CREG1 fold and showed that receptor binding alone does not confer growth suppression, separating binding from activity.

    Evidence 1.9-Å crystal structure with loop-deletion mutagenesis and growth assays

    PMID:16344469

    Open questions at the time
    • The FMN pocket is blocked but no enzymatic activity assigned
    • Structural basis of the activity beyond binding unknown
  4. 2004 Medium

    Connected CREG1 to MAPK signaling by showing it represses ERK1/2 to limit cardiomyocyte hypertrophy.

    Evidence Reciprocal overexpression/antisense in rat cardiomyocytes plus pressure-overload model

    PMID:15257182

    Open questions at the time
    • Mechanism of ERK1/2 regulation not molecular
    • Direct vs indirect effect unresolved
  5. 2010 Medium

    Defined two binding modes (glycosylation-dependent domains 7–10 and independent domains 11–13) and showed the independent mode suffices for cell-cycle arrest.

    Evidence In vitro binding with M6P/IGF2R domain fragments plus cell-cycle rescue in knockdown SMCs; combined with IGF-II endocytosis/PI3K-Akt findings

    PMID:18691225 PMID:19769965 PMID:21195083

    Open questions at the time
    • Structural basis of dual binding modes not solved
    • Single-lab vascular models
  6. 2015 High

    Reframed CREG1 as a lysosomal/autophagy regulator, showing it promotes lysosomal maturation and autophagic flux, partly via Rab7.

    Evidence Creg1+/- mice, adenoviral rescue in cardiomyocytes, chloroquine blockade

    PMID:25774384 PMID:27840305

    Open questions at the time
    • Molecular mechanism of lysosomal maturation control undefined
    • Link between secreted and intracellular pools unclear
  7. 2016 High

    Identified direct protein partners (Sec8) and transcriptional control (GATA1), expanding CREG1 mechanism beyond M6P/IGF2R.

    Evidence Co-IP and mutagenesis with KO-ES-cell rescue for Sec8; ChIP and promoter mutagenesis for GATA1

    PMID:27139506 PMID:27334848

    Open questions at the time
    • How Sec8 binding integrates with lysosomal roles unknown
    • GATA1 regulation tested mainly in endothelial context
  8. 2019 High

    Established CREG1 as a direct kinase inhibitor, binding ASK1 and TAK1 to suppress JNK1 and MAPK signaling in hepatocytes.

    Evidence Conditional hepatocyte KO/transgenic mice, co-IP, binding-domain mutagenesis, pathway-inhibitor epistasis

    PMID:28508477 PMID:30076625

    Open questions at the time
    • Structural basis of kinase binding not solved
    • Relationship to lysosomal/receptor functions unresolved
  9. 2021 High

    Consolidated CREG1 subcellular biology, localizing it to endolysosomes and mitochondria and defining roles in endocytosis, lysosomal biogenesis, and mitophagy with the HSPD1 partner.

    Evidence Validated immunofluorescence with KO controls, reciprocal gain/loss-of-function, tissue-specific KO, domain-mapped HSPD1 co-IP

    PMID:33726618 PMID:33966596

    Open questions at the time
    • Whether mitochondrial and lysosomal pools are functionally distinct unclear
    • Mechanism coupling CREG1 to membrane trafficking machinery incomplete
  10. 2024 Medium

    Extended CREG1 mechanism to ubiquitin-proteasome and ferroptosis control via defined axes (C-CBL-AMPKα1, FBXW7-FOXO1-PDK4) and to TGF-β/Smad2-Klf1-driven erythropoiesis.

    Evidence KO/transgenic mice, mass-spectrometry ubiquitination mapping, genetic rescue, zebrafish KO with Smad2 agonist rescue

    PMID:38272853 PMID:38953462 PMID:39094399

    Open questions at the time
    • Direct vs indirect control of E3 ligase expression unresolved
    • Single-lab mechanistic axes

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CREG1's many activities—receptor binding, kinase inhibition, lysosomal biogenesis, and transcriptional axes—are integrated by a single split-barrel protein with a blocked cofactor pocket remains unresolved.
  • No unifying biochemical activity assigned to the fold
  • Spatial/functional relationship between secreted and intracellular pools undefined
  • No human disease mutation reported in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005764 lysosome 3 GO:0005576 extracellular region 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 4 R-HSA-1640170 Cell Cycle 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ASK1HSPD1IGF2RMEK1/2RXRASEC8TAK1
Complex memberships
exocyst (via Sec8)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CREG is a secreted glycoprotein that enhances neuronal differentiation of NTERA-2 human embryonal carcinoma cells; media enriched in CREG promotes differentiation in the absence of retinoic acid, indicating CREG participates in an extracellular signaling cascade for pluripotent cell differentiation. Northern blot, constitutive overexpression in NTERA-2 cells, conditioned media treatment, morphological and gene expression analysis Oncogene Medium 10815803
2003 CREG binds directly to the mannose-6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) in a glycosylation-dependent manner, and M6P/IGF2R is required for CREG-induced G1/S cell cycle delay and growth inhibition. Direct binding assay, ectopic expression in NTERA-2 cells, cell cycle analysis in M6P/IGF2R-deficient cells Oncogene High 12934103
2005 Crystal structure of CREG at 1.9-Å resolution shows it forms a tight homodimer with a beta-barrel fold homologous to FMN-binding split-barrel proteins, but the FMN-binding pocket is sterically blocked. Glycosylation sites map to a patch opposite the dimer interface. A loop-deletion mutant retains overall structure, dimerization, and M6P/IGF2R binding but loses growth suppression activity, demonstrating that M6P/IGF2R binding is necessary but not sufficient for growth suppression. X-ray crystallography (1.9-Å resolution), site-directed mutagenesis, M6P/IGF2R binding assay, growth assay in NTERA-2 cells Proceedings of the National Academy of Sciences of the United States of America High 16344469
2004 CREG overexpression in neonatal rat cardiomyocytes inhibits cell growth and reduces ERK1/2 levels, dampening stretch-induced cardiomyocyte hypertrophy; antisense-mediated CREG knockdown produced the opposite effect, identifying CREG as a novel regulator of ERK1/2 in cardiac hypertrophy. Overexpression and antisense knockdown in cultured neonatal rat cardiomyocytes and fibroblasts, Western blot for ERK1/2, protein content and cell area measurements, in vivo pressure-overload rat model Journal of hypertension Medium 15257182
2008 CREG promotes a quiescent, differentiated smooth muscle cell (SMC) phenotype; retrovirus-mediated CREG transfer inhibits SMC dedifferentiation, proliferation, and synthesis of fibronectin, and reduces neointimal hyperplasia in balloon-injured rat carotid artery. ShRNA-mediated CREG knockdown abrogates serum starvation-induced SMC differentiation and growth arrest. Recombinant virus-mediated overexpression and shRNA knockdown in cultured SMCs, in vivo balloon injury rat carotid model, immunostaining, Western blot Cardiovascular research High 18267954
2008 Secreted CREG inhibits NIH3T3 fibroblast proliferation through M6P/IGF2R; CREG knockdown increases IGF-II levels and promotes proliferation, which is rescued by recombinant CREG in a concentration-dependent manner; CREG and M6P/IGF2R interaction confirmed by co-immunoprecipitation and immunofluorescence co-localization, and CREG expression correlates with receptor localization without affecting its expression. ShRNA knockdown, recombinant protein rescue, FACS, BrdU incorporation, immunoprecipitation-Western blot, immunofluorescence Genes to cells : devoted to molecular & cellular mechanisms Medium 18691225
2009 CREG inhibits SMC migration by mediating endocytosis and lysosomal trafficking of IGF-II via M6P/IGF2R; CREG knockdown increases IGF-II secretion and activates PI3K/Akt, promoting migration and MMP-9 activity. Blockade of IGF-II or IGF2R attenuated CREG knockdown-induced migration, and IGF2R antibody or soluble IGF2R fragment inhibited IGF-II endocytosis in CREG-overexpressing cells. Retroviral CREG overexpression and shRNA knockdown, migration assay, ELISA, endocytosis assay, Western blot for PI3K/Akt, neutralizing antibody and inhibitor blocking experiments Experimental cell research Medium 19769965
2010 CREG binds M6P/IGF2R at extracellular domains 7–10 in a glycosylation-dependent manner and at domains 11–13 in a glycosylation-independent manner; binding to domains 11–13 is sufficient to arrest cell cycle progression of CREG-knockdown SMCs, demonstrating a glycosylation-independent mode of action. Expression of glycosylation mutant CREG (mCREG) from HEK293 cells, in vitro binding assay with soluble M6P/IGF2R domain fragments, blocking with soluble fragments and neutralizing antibody, cell cycle analysis in CREG-knockdown SMCs Journal of molecular and cellular cardiology Medium 21195083
2011 CREG1 co-operates with p16(INK4a) to enhance cellular senescence; co-expression of CREG1 and p16(INK4a) has a greater effect than either alone in reducing cell growth, inducing cell cycle arrest, and inducing senescence in immortal Li-Fraumeni Syndrome fibroblasts, osteosarcoma, and fibrosarcoma lines. CREG1+p16(INK4a) inhibits cyclin A and cyclin B at the promoter/mRNA/protein level. Ectopic expression, co-expression studies, cell proliferation assays, senescence assays (SA-β-gal), cyclin promoter activity assays, RT-PCR, Western blot Cell cycle (Georgetown, Tex.) Medium 21263217
2011 CREG overexpression protects endothelial cells from apoptosis via the VEGF/PI3K/AKT signaling pathway; blocking with VEGF neutralizing antibody or PI3K inhibitors (LY294002, wortmannin) abrogated the anti-apoptotic effect of CREG. Gain- and loss-of-function in HUVECs and apoE-/- mouse arteries, TUNEL staining, caspase-3 assay, neutralizing antibody and PI3K inhibitor blocking Atherosclerosis Medium 21872252
2015 CREG1 is an evolutionarily conserved lysosomal protein that activates cardiomyocyte autophagy and promotes autophagic flux clearance; CREG1 deficiency impairs lysosomal maturation and reduces Rab7 expression, while restoration of CREG1 activates autophagy flux in cardiomyocytes. Chloroquine (lysosomal acidification inhibitor) blocked CREG1-mediated cardioprotection, confirming lysosomal autophagy as the mechanism. Creg1+/- mouse model, Ang II-induced myocardial fibrosis model, adenoviral overexpression in primary cardiomyocytes, Western blot (LC3II, beclin-1, p62, Rab7), chloroquine inhibitor studies Biochimica et biophysica acta High 25774384
2016 CREG1 directly interacts with the exocyst complex component Sec8; this interaction is required for cardiomyocyte differentiation and cell-cell cohesion. CREG1, Sec8, and N-cadherin co-localize at intercalated discs in vivo. CREG1 knockout inhibits the Sec8–N-cadherin interaction and induces their degradation, while CREG1 overexpression enhances adherens and gap junction assembly. Co-immunoprecipitation, site-directed mutagenesis of CREG1-Sec8 binding site, CREG1 KO ES cell rescue experiments, immunofluorescence co-localization, mouse ES cell to cardiomyocyte differentiation assay Stem cells (Dayton, Ohio) High 27334848
2016 CREG protects cardiomyocytes against MI/R injury-induced apoptosis by activating lysosomal autophagy; CREG involvement in lysosomal protein transfer improves cellular autophagy flux. In Creg+/- mice, dysfunctional autophagy (LC3A and p62 accumulation) and increased apoptosis were observed, while recombinant CREG infusion activated autophagy and reduced apoptosis. Chloroquine (autophagy blocker) abolished CREG protection. Creg+/- mice and recombinant CREG protein infusion, MI/R model (LAD ligation), Evans Blue-TTC staining, echocardiography, Western blot (LC3A, p62, cleaved caspase-3), TUNEL staining, chloroquine inhibitor Biochimica et biophysica acta. Molecular basis of disease High 27840305
2016 CREG transcription is regulated by the transcription factor GATA1 binding to the CREG promoter at position -297/-292; deletion mutation at this site disrupted GATA1 binding and reduced CREG transcription by ~83.3%. GATA1 overexpression abrogated high glucose/palmitate-induced HUVEC apoptosis through upregulation of CREG. Promoter-binding transcription-factor profiling array, ChIP assay, deletion mutation analysis, GATA1 overexpression in HUVECs, apoptosis assays PloS one Medium 27139506
2017 CREG directly interacts with apoptosis signal-regulating kinase 1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7-JNK1 (but not JNK2) signaling pathway; hepatocyte-specific CREG deletion exacerbated obesity, hepatic steatosis, and insulin resistance, while CREG overexpression was protective. JNK1 inhibition prevented the adverse effects of CREG deletion. Hepatocyte-specific CREG KO and overexpression mouse models, co-immunoprecipitation, Western blot for ASK1 phosphorylation and MKK4/7-JNK1 pathway, HFD and ob/ob models Hepatology (Baltimore, Md.) High 28508477
2019 Creg in hepatocytes suppresses MAPK signaling by directly binding to TAK1 (TGF-β-activated kinase 1) and inhibiting TAK1 phosphorylation; hepatocyte-specific CREG KO increased cell death and inflammatory cytokines after hepatic I/R. Mutating the TAK1-binding domain of CREG or pharmacologically inhibiting TAK1 abolished CREG protection, confirming the Creg-TAK1 interaction is required. Hepatocyte-specific Creg KO and transgenic mice, hepatic I/R model, hypoxia/reoxygenation in primary hepatocytes, molecular binding experiments (pull-down/co-IP), TAK1 binding domain mutagenesis, TAK1 inhibitor (5Z-7-ox) Hepatology (Baltimore, Md.) High 30076625
2019 CREG1 binds to retinoid X receptor α (RXRα), which interacts with thyroid hormone receptor to promote brown adipogenesis; CREG1 transgenic mice show elevated UCP1 and FGF-21 expression in BAT and WAT, increased browning, and resistance to diet-induced obesity. CREG1 transgenic mice, BAT primary cultures, co-binding/interaction assays for RXRα, UCP1 reporter assay, β3-adrenergic agonist challenge, metabolic phenotyping FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 30917000
2020 DNMT3B-mediated hypermethylation of the CREG promoter (at CG site +201/+202 bp) suppresses CREG expression by blocking binding of the transcription factor GR-α; ox-LDL increases DNMT3B expression, leading to CREG promoter hypermethylation and endothelial dysfunction. 5-aza-dC (DNMT inhibitor) restored CREG expression and activated p-eNOS/NO signaling. DNMT3B overexpression/inhibition in HUVECs, CREG promoter methylation analysis, ChIP for GR-α binding, 5-aza-dC treatment, site-specific methylation characterization Redox biology Medium 32067910
2021 CREG1 is mainly localized to the endosomal-lysosomal compartment (validated by antibodies through gain- and loss-of-function studies) and promotes both macropinocytosis and clathrin-dependent endocytosis, acidification of the endosomal-lysosomal compartment, and lysosomal biogenesis. CREG1 overexpression enhances autophagy and lysosome-mediated degradation; knockdown or knockout has opposite effects. Immunofluorescence microscopy with validated antibodies, gain- and loss-of-function (overexpression and KO), endocytosis assays, lysosomal acidification assay, autophagy flux assays Autophagy High 33966596
2021 CREG1 localizes to mitochondria in skeletal muscle cells and modulates mitophagy; CREG1 deficiency accelerates mitophagy induction (increased PINK1/PARKIN) and impairs mitochondrial quality. HSPD1/HSP60 (residues 401-573) directly interacts with CREG1 (residues 130-220) to antagonize CREG1 degradation and is involved in mitophagy regulation. Skeletal muscle-specific creg1 KO mice (Creg1;Ckm-Cre), recombinant CREG1 protein administration, electron microscopy, Western blot for PINK1/PARKIN/mitochondrial proteins, gain/loss-of-function in C2C12 cells, immunoprecipitation for HSPD1-CREG1 interaction, domain mapping Autophagy High 33726618
2021 CREG inhibits the phenotypic switching of cardiac fibroblasts to myofibroblasts after MI by suppressing CDC42 expression; recombinant CREG protein blocked hypoxia-induced proliferation and migration of cardiac fibroblasts through inhibition of CDC42. Creg+/- mice post-MI model, recombinant CREG protein treatment, in vitro hypoxia model with cardiac fibroblasts, Western blot for αSMA, collagen-1, CDC42, proliferation and migration assays Cell death & disease Medium 33824277
2022 CREG promotes differentiation of embryonic stem cells into smooth muscle cells through the TGF-β/Smad2/3 signaling pathway; CREG-KO ESCs showed significantly decreased SMC marker expression and reduced contractile capacity, while CREG-OE ESCs showed the opposite. CREG overexpression and shRNA KO in ESCs, SMC differentiation assay, Western blot for SMC markers (SM α-actin, SM22, calponin, SM-MHC), calcium ion assay, contractility assay Differentiation; research in biological diversity Medium 35349881
2022 CREG1 stimulates AMPK phosphorylation (at Thr172) and GLUT4 expression/glucose uptake in skeletal muscle cells through IGF2R; CREG1-induced AMPKα phosphorylation and 2-deoxyglucose uptake were suppressed by IGF2R knockdown and by Compound C (AMPK inhibitor), establishing CREG1-IGF2R-AMPK as a signaling axis. CREG1 treatment of C2C12 myotubes, IGF2R knockdown, AMPK inhibitor (Compound C), Western blot for phospho-AMPKα, GLUT4, 2-deoxyglucose uptake assay, CTX-induced muscle regeneration mouse model Biochemical and biophysical research communications Medium 36528955
2023 CREG1 inhibits LAMP2 protein degradation by suppressing the expression of F-box protein 27 (FBXO27), thereby promoting autophagy in cardiomyocytes; LAMP2 overexpression reversed the effect of CREG1 knockdown on palmitate-induced inhibition of cardiomyocyte autophagy, defining a CREG1-FBXO27-LAMP2 axis. Cardiac-specific Creg1 KO and transgenic mice, diabetic cardiomyopathy model, palmitate-stimulated NMCMs, Western blot, CREG1 overexpression and knockdown with adenovirus/siRNA, LAMP2 overexpression rescue Experimental & molecular medicine Medium 37658156
2023 CREG1 directly interacts with MEK1/2 and promotes MEK1/2 phosphorylation in megakaryocytes; CREG1 deficiency impairs actin cytoskeleton, proplatelet formation, and ploidy, causing thrombocytopenia due to inefficient bone marrow thrombocytopoiesis. Megakaryocyte/platelet conditional KO and transgenic mice, cytosine arabinoside thrombocytopenia model, immunoprecipitation for MEK1/2-CREG1, Western blot for MEK1/2 phosphorylation, F-actin staining, ploidy assay International journal of biological sciences Medium 37496998
2024 CREG1 deficiency inhibits myoblast differentiation and skeletal muscle regeneration by promoting C-CBL E3-ubiquitin ligase-mediated K48-linked polyubiquitination and degradation of AMPKα1 at K396; silencing C-CBL in CREG1 knockout mice significantly improved muscle regeneration, establishing CREG1-C-CBL-AMPKα1 as a regulatory axis. Creg1 KO and satellite cell-specific overexpression mice (AAV9), cardiotoxin muscle injury model, mass spectrometry, RNA-seq, AAV-sh-C-Cbl rescue, Western blot for AMPKα1 ubiquitination, C2C12 cell transfection Journal of cachexia, sarcopenia and muscle Medium 38272853
2024 CREG1 inhibits ferroptosis in cardiomyocytes by suppressing PDK4 mRNA and protein expression through the FBXW7-FOXO1 signaling pathway; CREG1-FBXW7-FOXO1-PDK4 is a defined mechanistic axis, and PDK4 deficiency reverses the effects of CREG1 knockdown on DOX-induced ferroptosis. CREG1 transgenic and cardiac-specific KO mice, DOX-induced cardiotoxicity model, transcriptomics, immunoprecipitation, siRNA knockdown of PDK4, Western blot Redox biology Medium 39094399
2024 CREG1 promotes exosome genesis and release in bovine placental trophoblast cells by targeting IGF2R; IGF2R knockdown inhibited exosome genesis and blocked CREG1-induced exosome production. IGF2R can also reverse-regulate CREG1 expression. CREG1 binding to IGF2R subsequently activates Rab11 to facilitate exosome release. Creg1 overexpression and Igf2r siRNA knockdown in bovine trophoblast cells, exosome isolation and quantification, co-immunoprecipitation, Western blot International journal of biological macromolecules Low 38917918
2024 In zebrafish, loss of creg1 causes anemia due to defective erythroid differentiation and excessive apoptosis of erythroid progenitors; mechanistically, creg1 deficiency reduces TGF-β/Smad2 signaling pathway activation, and Klf1 is a downstream target of this pathway required for normal erythropoiesis. Treatment with a Smad2 agonist (IDE2) restores erythroid development in creg1-/- mutants. Zebrafish creg1 knockout, scRNA-seq, Smad2 agonist (IDE2) rescue, gene expression analysis, epistasis with Klf1 Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 38953462
2025 CREG1-IGF2R-PI3K-AKT signaling mediates TREM2+ macrophage-promoted osteogenic differentiation of ligament-derived progenitor cells in ankylosing spondylitis; TREM2+ macrophages secrete CREG1 to drive pathological new bone formation, and targeting this axis alleviates new bone formation in a collagen antibody-induced arthritis model. TREM2+ macrophage depletion and Trem2 knockout in CAIA model, CREG1 secretion assay, CREG1-IGF2R-PI3K-AKT pathway inhibition, osteogenic differentiation of LDPCs Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40091508
2025 CREG1 is localized to endolysosomal and autophagosomal compartments in cardiomyocytes; loss of CREG1 impairs autophagy flux and mitophagy by impairing autophagosome membrane expansion and degradation. Global Creg1 KO mice develop cardiac hypertrophy, fibrosis, and diastolic dysfunction at ~80 weeks; cardiomyocyte-specific CREG1 overexpression (KI) enhances exercise capacity under nutritional stress. Global Creg1 KO (entire ORF deletion) and Rosa26-CREG1 KI mice, cm-specific Creg1 KO and KI, autophagy reporter (CAG-EGFP-RFP-LC3), electron microscopy, biochemical autophagy assays, cardiac phenotyping bioRxiv : the preprint server for biologypreprint Medium 41292877
2020 CREG1 is cleaved by cathepsin B in vitro, and cathepsin B overexpression reduces secreted CREG1 levels while cathepsin B deletion or inhibition increases them; reduced CREG1 expression promotes proliferation, migration, and invasion of PyMT breast tumor cells, establishing cathepsin B as a negative regulator of CREG1 in the tumor microenvironment. Cathepsin B overexpression/deletion in MMTV-PyMT mouse model, in vitro cleavage assay, conditioned media/tumor interstitial fluid proteomics (SILAC), recombinant CREG1 treatment, orthotopic transplantation Cellular and molecular life sciences : CMLS Medium 32385587

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The secreted glycoprotein CREG enhances differentiation of NTERA-2 human embryonal carcinoma cells. Oncogene 83 10815803
2003 The secreted glycoprotein CREG inhibits cell growth dependent on the mannose-6-phosphate/insulin-like growth factor II receptor. Oncogene 80 12934103
2019 Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1-Dependent Manner in Mice. Hepatology (Baltimore, Md.) 63 30076625
2016 CREG protects from myocardial ischemia/reperfusion injury by regulating myocardial autophagy and apoptosis. Biochimica et biophysica acta. Molecular basis of disease 60 27840305
2008 CREG promotes a mature smooth muscle cell phenotype and reduces neointimal formation in balloon-injured rat carotid artery. Cardiovascular research 50 18267954
2005 The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation. Proceedings of the National Academy of Sciences of the United States of America 50 16344469
2020 DNA hypermethylation: A novel mechanism of CREG gene suppression and atherosclerogenic endothelial dysfunction. Redox biology 43 32067910
2021 CREG1 improves the capacity of the skeletal muscle response to exercise endurance via modulation of mitophagy. Autophagy 38 33726618
2017 The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance. Hepatology (Baltimore, Md.) 36 28508477
2015 CREG1 ameliorates myocardial fibrosis associated with autophagy activation and Rab7 expression. Biochimica et biophysica acta 36 25774384
2011 CREG1 enhances p16(INK4a) -induced cellular senescence. Cell cycle (Georgetown, Tex.) 35 21263217
2011 Overexpression of CREG attenuates atherosclerotic endothelium apoptosis via VEGF/PI3K/AKT pathway. Atherosclerosis 33 21872252
2023 The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes. Experimental & molecular medicine 32 37658156
2004 CREG, a new regulator of ERK1/2 in cardiac hypertrophy. Journal of hypertension 32 15257182
2018 The Structure and Biological Function of CREG. Frontiers in cell and developmental biology 27 30416997
2024 CREG1 attenuates doxorubicin-induced cardiotoxicity by inhibiting the ferroptosis of cardiomyocytes. Redox biology 25 39094399
2016 CREG1 Interacts with Sec8 to Promote Cardiomyogenic Differentiation and Cell-Cell Adhesion. Stem cells (Dayton, Ohio) 25 27334848
1990 Allodeterminants and evolution of a novel HLA-B5 CREG antigen, HLA-B SNA. Journal of immunology (Baltimore, Md. : 1950) 25 1691230
2008 Secreted CREG inhibits cell proliferation mediated by mannose 6-phosphate/insulin-like growth factor II receptor in NIH3T3 fibroblasts. Genes to cells : devoted to molecular & cellular mechanisms 24 18691225
2017 CREG1 heterozygous mice are susceptible to high fat diet-induced obesity and insulin resistance. PloS one 23 28459882
2021 CREG1 promotes lysosomal biogenesis and function. Autophagy 21 33966596
2003 Undifferentiated spondyloarthropathies in Brazilians: importance of HLA-B27 and the B7-CREG alleles in characterization and disease progression. The Journal of rheumatology 21 14719206
2002 Identification and characterization of novel members of the CREG family, putative secreted glycoproteins expressed specifically in brain. Genomics 21 12408961
2019 CREG1 stimulates brown adipocyte formation and ameliorates diet-induced obesity in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 30917000
2013 Nanoporous CREG-eluting stent attenuates in-stent neointimal formation in porcine coronary arteries. PloS one 20 23573278
2009 CREG inhibits migration of human vascular smooth muscle cells by mediating IGF-II endocytosis. Experimental cell research 20 19769965
2019 CREG1 promotes uncoupling protein 1 expression and brown adipogenesis in vitro. Journal of biochemistry 19 30295852
2010 Glycosylation-independent binding to extracellular domains 11-13 of mannose-6-phosphate/insulin-like growth factor-2 receptor mediates the effects of soluble CREG on the phenotypic modulation of vascular smooth muscle cells. Journal of molecular and cellular cardiology 19 21195083
2024 CREG1 deficiency impaired myoblast differentiation and skeletal muscle regeneration. Journal of cachexia, sarcopenia and muscle 16 38272853
2018 Transplantation of CREG modified embryonic stem cells improves cardiac function after myocardial infarction in mice. Biochemical and biophysical research communications 15 29684345
2016 Up-Regulation of CREG Expression by the Transcription Factor GATA1 Inhibits High Glucose- and High Palmitate-Induced Apoptosis in Human Umbilical Vein Endothelial Cells. PloS one 15 27139506
2021 CREG ameliorates the phenotypic switching of cardiac fibroblasts after myocardial infarction via modulation of CDC42. Cell death & disease 14 33824277
2016 Glycoproteomic Approach Identifies KRAS as a Positive Regulator of CREG1 in Non-small Cell Lung Cancer Cells. Theranostics 13 26722374
2021 GATA3 improves the protective effects of bone marrow-derived mesenchymal stem cells against ischemic stroke induced injury by regulating autophagy through CREG. Brain research bulletin 12 34500038
2010 Pattern of expression of the CREG gene and CREG protein in the mouse embryo. Molecular biology reports 12 20857207
2014 CREG promotes vasculogenesis by activation of VEGF/PI3K/Akt pathway. Frontiers in bioscience (Landmark edition) 11 24896346
2013 CREG promotes the proliferation of human umbilical vein endothelial cells through the ERK/cyclin E signaling pathway. International journal of molecular sciences 11 24018888
2010 Increased expression of cellular repressor of E1A-stimulated gene (CREG) in gastric cancer patients: a mechanism of proliferation and metastasis in cancer. Digestive diseases and sciences 11 21132365
1989 HLA-B SNA antigen: a BW6 associated B locus antigen belonging to the B5 CREG. Tissue antigens 11 2741166
2025 CREG1 attenuates intervertebral disc degeneration by alleviating nucleus pulposus cell pyroptosis via the PINK1/Parkin-related mitophagy pathway. International immunopharmacology 9 39746276
2025 IL-33-Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1-IGF2R Axis in Ankylosing Spondylitis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 9 40091508
2022 CREG ameliorates embryonic stem cell differentiation into smooth muscle cells by modulation of TGF-β expression. Differentiation; research in biological diversity 9 35349881
2023 PABPN1 promotes clear cell renal cell carcinoma progression by suppressing the alternative polyadenylation of SGPL1 and CREG1. Carcinogenesis 8 37452741
2022 CREG1 stimulates AMPK phosphorylation and glucose uptake in skeletal muscle cells. Biochemical and biophysical research communications 8 36528955
2018 Antiapoptotic role of the cellular repressor of E1A-stimulated genes (CREG) in retinal photoreceptor cells in a rat model of light-induced retinal injury. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 29864918
2014 CREG1 promotes angiogenesis and neovascularization. Frontiers in bioscience (Landmark edition) 8 24896341
1983 CREG antigens differentially influence expression of extraarticular manifestations in whites and blacks with rheumatoid arthritis. Seminars in arthritis and rheumatism 8 6673112
2023 CREG Protects Retinal Ganglion Cells loss and Retinal Function Impairment Against ischemia-reperfusion Injury in mice via Akt Signaling Pathway. Molecular neurobiology 7 37402034
2024 CREG1 promotes bovine placental trophoblast cells exosome release by targeting IGF2R and participates in regulating organoid differentiation via exosomes transport. International journal of biological macromolecules 6 38917918
2023 The role of CREG1 in megakaryocyte maturation and thrombocytopoiesis. International journal of biological sciences 6 37496998
2022 CREG1 administration stimulates BAT thermogenesis and improves diet-induced obesity in mice. Journal of biochemistry 6 34647124
2021 Shrimp Plasma CREG Is a Hemocyte Activation Factor. Frontiers in immunology 6 34484206
2020 CREG improves cardiac function by regulating cardiomyocytes' autophagy in diabetic myocardial infarction rats. European review for medical and pharmacological sciences 6 33215442
2020 The secreted inhibitor of invasive cell growth CREG1 is negatively regulated by cathepsin proteases. Cellular and molecular life sciences : CMLS 5 32385587
2012 CREG: a possible candidate for both prevention and treatment of proliferative vascular disease. Current molecular medicine 5 22834829
2012 CREG mediated adventitial fibroblast phenotype modulation: a possible therapeutic target for proliferative vascular disease. Medical hypotheses 4 22543074
2025 CREG1 alleviates bone loss in osteoporosis by enhancing the osteogenic differentiation of BMSCs through mitophagy. International immunopharmacology 3 40378431
2024 Creg1 Regulates Erythroid Development via TGF-β/Smad2-Klf1 Axis in Zebrafish. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 38953462
2022 CREG1 improves diet-induced obesity via uncoupling protein 1-dependent manner in mice. Genes to cells : devoted to molecular & cellular mechanisms 2 35007381
2022 CREG mitigates neonatal HIE injury through survival promotion and apoptosis inhibition in hippocampal neurons via activating AKT signaling. Cell biology international 2 35143104
2002 Eight new HLA-A alleles associated with antigens in the A2 CREG. Tissue antigens 1 12028541
2002 Seven new HLA-B alleles associated with antigens in the B7 CREG. Tissue antigens 1 12074716
2026 CREG1 promotes bone formation via targeting RAB7 to activate autophagy in osteoporosis. Cellular signalling 0 41577020
2026 CREG1 restricts ALV-J replication via the mitochondrial dysfunction-driven activation of innate immunity and apoptosis. Frontiers in immunology 0 41646965
2026 CREG1 Attenuates Osteoarthritis Progression by Suppressing Chondrocyte Pyroptosis Through the PINK1/Parkin-Mediated Mitophagy Pathway. Biotechnology journal 0 41693246
2025 The mechanism by which MALAT1/CREG1 regulates premature rupture of fetal membrane through autophagy mediated differentiation of amniotic fibroblasts. Non-coding RNA research 0 40297152
2025 Novel roles for CREG1 in hematopoiesis revealed by single-cell RNA sequencing. Cell & bioscience 0 40452027
2025 CREG1 promotes autophagy and protects the heart against nutritional stress-induced injury and age-associated hypertrophy, fibrosis and diastolic dysfunction. bioRxiv : the preprint server for biology 0 41292877
2010 [Purification and functional identification of the recombinant human CREG/myc-His glycoprotein]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 0 21038674
2002 Description of six new HLA-B alleles in the 5C CREG including a B*58 intron two sequence. Tissue antigens 0 12028545
2002 [Selection of donor in mismatched hematopoietic stem cell transplantation by CREG, residue match and HLA three-dimensional structure]. Zhongguo shi yan xue ye xue za zhi 0 12513720

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