Affinage

CREG1

Protein CREG1 · UniProt O75629

Length
220 aa
Mass
24.1 kDa
Annotated
2026-04-28
71 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CREG1 is a secreted, endosomal-lysosomal glycoprotein that promotes cellular differentiation, suppresses proliferation, and maintains lysosomal-autophagic homeostasis across diverse tissues. Structurally, CREG1 forms a homodimer with a β-barrel fold that binds the mannose-6-phosphate/IGF2 receptor (M6P/IGF2R) through both glycosylation-dependent (domains 7–10) and glycosylation-independent (domains 11–13) sites, facilitating IGF-II endocytosis and attenuating IGF-II-driven PI3K/Akt signaling to inhibit cell growth and migration (PMID:12934103, PMID:16344469, PMID:21195083, PMID:19769965). CREG1 localizes to the endosomal-lysosomal compartment where it promotes lysosomal biogenesis, endocytic trafficking, autophagic flux, and mitophagy—functions whose loss leads to autophagosome accumulation, impaired Rab7 expression, and organ-level pathology including cardiac fibrosis and skeletal muscle dysfunction (PMID:33966596, PMID:25774384, PMID:33726618). Beyond its lysosomal roles, CREG1 directly engages cytoplasmic kinases ASK1 and TAK1 to suppress MAPK-mediated stress signaling in liver, interacts with exocyst subunit Sec8 to drive intercalated disc assembly during cardiomyocyte differentiation, and cooperates with p16(INK4a) to enforce cellular senescence through transcriptional repression of cyclins A and B (PMID:28508477, PMID:30076625, PMID:27334848, PMID:21263217).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 Medium

    The first functional characterization established that CREG1 is a secreted glycoprotein that promotes differentiation of embryonal carcinoma cells, positioning it as an extracellular differentiation signal rather than a transcription factor or intracellular enzyme.

    Evidence Northern blot, overexpression in NTERA-2 cells, conditioned media experiments

    PMID:10815803

    Open questions at the time
    • Receptor or binding partner mediating extracellular signaling unknown
    • Mechanism of differentiation induction not defined
  2. 2003 High

    The identification of M6P/IGF2R as the required receptor for CREG1's antiproliferative activity established a specific receptor–ligand axis, resolving how a secreted glycoprotein inhibits cell growth.

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

    PMID:12934103

    Open questions at the time
    • Binding site on M6P/IGF2R not mapped
    • Downstream intracellular signal unknown
  3. 2005 High

    The 1.9 Å crystal structure revealed CREG1 as a homodimeric β-barrel protein that cannot bind FMN despite structural homology, and mutagenesis showed that M6P/IGF2R binding is necessary but not sufficient for growth suppression—an additional surface element is required.

    Evidence X-ray crystallography, loop-deletion mutagenesis, M6P/IGF2R binding and growth assays

    PMID:16344469

    Open questions at the time
    • Identity of the additional surface required for growth suppression unknown
    • No co-crystal with receptor
  4. 2008 High

    Reciprocal gain- and loss-of-function studies in vascular smooth muscle cells and in vivo balloon injury models demonstrated that CREG1 maintains differentiated SMC phenotype and inhibits neointimal hyperplasia, extending its role from embryonal carcinoma to cardiovascular biology.

    Evidence Retroviral overexpression/shRNA, in vivo balloon injury model in SMCs

    PMID:18267954

    Open questions at the time
    • Whether SMC effects depend entirely on M6P/IGF2R unclear
    • Downstream transcriptional targets not identified
  5. 2008 High

    The demonstration that CREG1 facilitates IGF-II endocytosis via M6P/IGF2R and that CREG knockdown elevates IGF-II secretion resolved the mechanism by which CREG1–M6P/IGF2R interaction suppresses proliferation: by clearing a mitogenic ligand.

    Evidence Co-immunoprecipitation, FACS, endocytosis assay in NIH3T3 cells

    PMID:18691225

    Open questions at the time
    • Whether CREG1 alters M6P/IGF2R trafficking dynamics unknown
    • Role of glycosylation-independent binding not addressed
  6. 2009 High

    Epistatic experiments showed CREG1 suppresses SMC migration by reducing IGF-II-driven PI3K/Akt/MMP-9 signaling through enhanced IGF-II endocytosis, unifying its antiproliferative and anti-migratory activities under one receptor-clearance mechanism.

    Evidence Migration assay, neutralizing antibody and PI3K inhibitor epistasis, endocytosis assay

    PMID:19769965

    Open questions at the time
    • MMP-9 regulatory step not precisely defined
    • Whether CREG1 has M6P/IGF2R-independent anti-migratory activity untested
  7. 2010 High

    Mapping CREG1 binding to two distinct M6P/IGF2R regions (domains 7–10, glycosylation-dependent; domains 11–13, glycosylation-independent) showed that CREG1 engages the receptor through a bimodal mechanism, each sufficient for growth arrest.

    Evidence In vitro binding with glycosylation-mutant CREG, soluble receptor fragment blocking, cell cycle analysis

    PMID:21195083

    Open questions at the time
    • Structural basis of glycosylation-independent binding undetermined
    • Whether both sites are engaged simultaneously unknown
  8. 2011 Medium

    CREG1 was shown to cooperate with p16(INK4a) to enforce cellular senescence by transcriptionally repressing cyclins A and B, revealing an intracellular gene-regulatory function distinct from its extracellular receptor-binding activity.

    Evidence Co-expression experiments, promoter-reporter assays, SA-β-gal senescence assay

    PMID:21263217

    Open questions at the time
    • Whether CREG1 directly contacts cyclin promoters or acts through an intermediary not resolved
    • Single lab, not replicated
  9. 2015 High

    The discovery that CREG1 haploinsufficiency impairs lysosomal maturation, reduces Rab7, and causes autophagosome accumulation with defective autophagic flux in vivo redefined CREG1 as a lysosomal biogenesis factor, not merely an extracellular ligand.

    Evidence Creg1+/− mice, recombinant CREG1 rescue, chloroquine confirmation, Western blot

    PMID:25774384

    Open questions at the time
    • How CREG1 regulates Rab7 expression molecularly unknown
    • Whether lysosomal role is M6P/IGF2R-dependent not tested
  10. 2016 High

    Identification of Sec8 (exocyst complex) as a direct CREG1 binding partner required for intercalated disc assembly and cardiomyocyte differentiation established a new non-lysosomal, cytoskeleton-linked role for CREG1.

    Evidence Co-IP, site-directed mutagenesis, CREG1 KO ES cell rescue, co-localization imaging

    PMID:27334848

    Open questions at the time
    • Whether CREG1–Sec8 interaction is conserved beyond cardiomyocytes unknown
    • Mechanism by which CREG1 stabilizes N-cadherin via Sec8 unclear
  11. 2017 High

    Direct binding of CREG1 to ASK1 and inhibition of ASK1 phosphorylation, confirmed by JNK1-specific epistasis, established a hepatocyte-intrinsic MAPK-suppressive function protecting against steatosis.

    Evidence Hepatocyte-specific CREG1 KO/OE mice, Co-IP, JNK1 inhibitor epistasis

    PMID:28508477

    Open questions at the time
    • Binding interface between CREG1 and ASK1 not structurally resolved
    • Whether this kinase inhibition is catalytic or sequestration-based unknown
  12. 2019 High

    The finding that CREG1 directly binds TAK1 and inhibits its phosphorylation to suppress MAPK signaling during hepatic ischemia/reperfusion extended the kinase-inhibitory paradigm to a second MAP3K, validated by binding-domain mutagenesis.

    Evidence Hepatocyte-specific KO/Tg mice, Co-IP, TAK1-binding domain mutation, TAK1 inhibitor blocking

    PMID:30076625

    Open questions at the time
    • Structural basis of TAK1 vs ASK1 selectivity unknown
    • Whether CREG1 inhibits kinases in other tissues untested
  13. 2021 High

    Systematic validation of CREG1 as an endosomal-lysosomal resident that promotes macropinocytosis, clathrin-dependent endocytosis, endolysosomal acidification, and lysosomal biogenesis unified its diverse phenotypic effects under a core endolysosomal function.

    Evidence Validated antibodies, KO/KD/OE, acridine orange staining, transferrin uptake, LAMP1/cathepsin D assays

    PMID:33966596

    Open questions at the time
    • Molecular mechanism by which CREG1 promotes acidification undetermined
    • Whether CREG1 functions as a lumenal or membrane-associated factor unclear
  14. 2021 High

    Skeletal muscle-specific Creg1 KO revealed CREG1 as a mitophagy regulator that localizes to mitochondria and interacts with HSPD1/HSP60, broadening the autophagic role to organelle-selective degradation.

    Evidence Skeletal muscle-specific Creg1 KO, electron microscopy, Co-IP mapping CREG1(130–220)–HSPD1(401–573)

    PMID:33726618

    Open questions at the time
    • Whether CREG1 is imported into mitochondria or tethers from the OMM unclear
    • Relationship between HSPD1 interaction and PINK1/Parkin pathway not established
  15. 2023 Medium

    Discovery that CREG1 stabilizes LAMP2 by suppressing FBXO27 E3 ligase expression provided a molecular mechanism for CREG1's lysosomal maintenance function, validated by LAMP2 rescue of CREG1 knockdown in diabetic cardiomyopathy.

    Evidence Cardiac-specific KO/Tg mice, LAMP2 overexpression rescue, FBXO27 expression analysis

    PMID:37658156

    Open questions at the time
    • How CREG1 suppresses FBXO27 expression not defined
    • Single lab
  16. 2023 Medium

    Identification of direct CREG1–MEK1/2 interaction promoting MEK phosphorylation for megakaryocyte maturation revealed a context-dependent pro-kinase activity, contrasting with the ASK1/TAK1 kinase-inhibitory roles.

    Evidence Megakaryocyte/platelet conditional Creg1 KO and Tg mice, Co-IP, actin staining

    PMID:37496998

    Open questions at the time
    • Mechanism of opposing kinase modulation (activation vs inhibition) in different contexts unresolved
    • Single lab
  17. 2024 Medium

    CREG1 was shown to maintain satellite cell differentiation and muscle regeneration by preventing C-CBL-mediated K48-polyubiquitination of AMPKα1 at K396, linking CREG1 to ubiquitin-proteasome regulation of a master metabolic kinase.

    Evidence Satellite cell-specific OE and myofibre-specific KO mice, mass spectrometry, AAV-shC-CBL rescue

    PMID:38272853

    Open questions at the time
    • Whether CREG1 directly binds C-CBL or AMPKα1 not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how CREG1 exerts opposing effects on different kinases (inhibiting ASK1/TAK1 yet activating MEK1/2), whether its lysosomal and extracellular receptor-binding functions are mechanistically linked or independent, and what molecular event converts CREG1 from a secreted ligand to an endolysosomal/mitochondrial effector.
  • No unified model explains context-dependent kinase activation vs inhibition
  • Whether intracellular CREG1 re-enters the secretory pathway or acts cell-autonomously after synthesis is unresolved
  • No co-crystal structure of CREG1 with any intracellular partner exists

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005764 lysosome 3 GO:0005576 extracellular region 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-9612973 Autophagy 5 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ASK1EXOC4HSPD1IGF2RMEK1RXRATAK1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CREG1 is a secreted glycoprotein that enhances neuronal differentiation of NTERA-2 embryonal carcinoma cells; CREG mRNA is induced during differentiation of mouse embryonic stem cells and human NTERA-2 cells, and secreted CREG in conditioned media promotes differentiation in the absence of retinoic acid, indicating it participates in an extracellular signaling cascade. Northern blot, constitutive overexpression in NTERA-2 cells, conditioned media experiments Oncogene Medium 10815803
2003 CREG1 inhibits cell growth and delays G1/S transition dependent on its glycosylation-mediated direct binding to the mannose-6-phosphate/IGF2 receptor (M6P/IGF2R); cells lacking M6P/IGF2R are resistant to CREG-induced growth inhibition, establishing M6P/IGF2R as required for CREG's antiproliferative activity. Direct binding assay, cell cycle analysis, gain-of-function in M6P/IGF2R-deficient cells Oncogene High 12934103
2005 Crystal structure of CREG1 resolved to 1.9 Å reveals it forms a tight homodimer with a β-barrel fold structurally homologous to FMN-binding split-barrel proteins, but a loop and bulky residues sterically block the FMN-binding pocket so CREG1 cannot bind FMN. Glycosylation sites cluster opposite the dimer interface, likely presenting bivalent ligand to M6P/IGF2R. A loop-deletion mutant retains dimerization and M6P/IGF2R binding but loses growth suppression activity, showing M6P/IGF2R binding is necessary but not sufficient for growth inhibition. X-ray crystallography (1.9 Å), structure-based mutagenesis, M6P/IGF2R binding assay, growth assay Proceedings of the National Academy of Sciences of the United States of America High 16344469
2008 CREG1 promotes the quiescent, differentiated smooth muscle cell (SMC) phenotype: retroviral CREG overexpression enhances SMC differentiation, inhibits proliferation, and reduces fibronectin synthesis; CREG knockdown via shRNA abrogates serum starvation-induced SMC differentiation and growth arrest. In vivo, CREG is downregulated after balloon injury and retroviral CREG transfer inhibits SMC dedifferentiation, proliferation, and neointimal hyperplasia. Retroviral gain- and loss-of-function (shRNA), Western blot, immunostaining, in vivo balloon injury model Cardiovascular research High 18267954
2008 Secreted CREG1 inhibits NIH3T3 fibroblast proliferation via M6P/IGF2R; CREG knockdown increases IGF-II secretion and promotes proliferation, which is reversed by recombinant CREG protein in a concentration-dependent manner. Direct CREG–M6P/IGF2R interaction was confirmed by co-immunoprecipitation and immunofluorescence. CREG expression correlates with M6P/IGF2R intracellular localization, and CREG facilitates IGF-II endocytosis through M6P/IGF2R. Co-immunoprecipitation, immunofluorescence, FACS, BrdU incorporation, ELISA, endocytosis assay Genes to cells High 18691225
2009 CREG1 inhibits SMC migration by promoting IGF-II endocytosis through M6P/IGF2R, reducing IGF-II–driven PI3K/Akt activation and MMP-9 activity; blocking IGF-II or PI3K abolishes the pro-migratory effect of CREG knockdown, and blocking IGF-II binding to M6P/IGF2R attenuates IGF-II endocytosis in CREG-overexpressing cells. Retroviral overexpression/shRNA knockdown, migration assay, ELISA, endocytosis assay, Western blot, neutralizing antibody/pharmacological inhibitor epistasis Experimental cell research High 19769965
2010 CREG1 binds to M6P/IGF2R extracellular domains 7–10 in a glycosylation-dependent manner and to domains 11–13 in a glycosylation-independent manner; both binding sites are sufficient for CREG-mediated SMC proliferation arrest, demonstrating that glycosylation is not absolutely required for biological activity. In vitro binding assay with wild-type and glycosylation-mutant CREG proteins, soluble M6P/IGF2R fragment blocking, neutralizing antibody, cell cycle analysis Journal of molecular and cellular cardiology High 21195083
2011 CREG1 enhances p16(INK4a)-induced cellular senescence; co-expression of CREG1 and p16(INK4a) has greater effects than either alone on reducing cell growth, inducing cell cycle arrest, and senescence. The cooperative effect involves transcriptional repression of cyclin A and cyclin B promoter activities. CREG1 expression is silenced by promoter DNA methylation during immortalization. Ectopic expression, co-expression experiments, promoter-reporter assays, RT-PCR, Western blot, SA-β-gal senescence assay Cell cycle Medium 21263217
2011 CREG1 protects endothelial cells from apoptosis via activation of the VEGF/PI3K/AKT signaling pathway; blocking VEGF neutralizing antibody or PI3K inhibitor (LY294002/wortmannin) abolished the anti-apoptotic effect of CREG overexpression, placing CREG upstream of VEGF/PI3K/Akt. Adenoviral overexpression, shRNA knockdown, caspase-3 activity assay, TUNEL, neutralizing antibody and pharmacological inhibitor blocking Atherosclerosis Medium 21872252
2004 CREG1 inhibits cardiac cell growth as a regulator of ERK1/2; overexpression reduces protein content, cell area, and ERK1/2 levels in neonatal cardiomyocytes and dampens stretch-induced hypertrophy through ERK1/2, while antisense inhibition of CREG has opposite effects without altering PKC isoforms, JNK1/2, p38, or apoptotic signals. Overexpression/antisense inhibition in neonatal rat cardiomyocytes, Western blot, in vivo pressure-overload model, Northern blot Journal of hypertension Medium 15257182
2015 CREG1 is an evolutionarily conserved lysosomal protein; its deficiency in Creg1+/- mice impairs lysosomal maturation, reduces Rab7 expression, and leads to autophagosome accumulation (elevated LC3II, beclin-1) with impaired autophagic flux (elevated p62), resulting in aggravated myocardial fibrosis. Restoration of CREG1 activates cardiac autophagy and reverses fibrosis. Chloroquine confirmed the lysosomal mechanism. Creg1+/- mouse model, recombinant CREG1 infusion, adenoviral overexpression/silencing in cardiomyocytes, Western blot, chloroquine inhibitor experiments Biochimica et biophysica acta High 25774384
2016 CREG1 directly interacts with Sec8 of the exocyst complex; site-directed mutagenesis showed CREG1 binding to Sec8 is required for cardiomyocyte differentiation and cell-cell cohesion. CREG1, Sec8, and N-cadherin co-localize at intercalated discs. CREG1 overexpression enhances adherens and gap junction assembly, while CREG1 knockout inhibits Sec8–N-cadherin interaction and induces their degradation. Co-immunoprecipitation, site-directed mutagenesis, rescue of CREG1 KO ES cells, co-localization imaging, gain/loss-of-function differentiation assay Stem cells High 27334848
2016 CREG1 protects against MI/R injury by activating lysosomal autophagy to suppress cardiomyocyte apoptosis; Creg1+/- mice show dysfunctional autophagy (LC3A and p62 accumulation) and increased apoptosis after MI/R. Recombinant CREG1 infusion activates autophagy and reduces apoptosis. Chloroquine (autophagy blocker) abolishes CREG1-mediated cardioprotection, confirming the lysosomal autophagy mechanism. Creg1+/- mice, recombinant CREG1 infusion, chloroquine blocking, Western blot, TUNEL, TTC staining, echocardiography Biochimica et biophysica acta. Molecular basis of disease High 27840305
2017 CREG1 directly interacts with apoptosis signal-regulating kinase 1 (ASK1) and inhibits ASK1 phosphorylation, thereby blocking the downstream MKK4/7-JNK1 signaling pathway; JNK1 (but not JNK2) inhibition prevents the adverse effects of CREG deletion on hepatic steatosis and metabolic disorders, placing CREG upstream of ASK1-JNK1. Hepatocyte-specific CREG KO and overexpression mice, direct interaction assay (immunoprecipitation), JNK1 inhibition epistasis, Western blot Hepatology High 28508477
2019 CREG1 in hepatocytes protects against liver ischemia/reperfusion injury by binding to TAK1 and inhibiting TAK1 phosphorylation, thereby suppressing downstream MAPK signaling; mutating the TAK1-binding domain of CREG or pharmacological TAK1 inhibition (5Z-7-ox) abolishes the protective effect of CREG. Hepatocyte-specific CREG KO and transgenic mice, I/R injury model, co-immunoprecipitation, TAK1-binding domain mutation, TAK1 inhibitor blocking, Western blot Hepatology High 30076625
2019 CREG1 binds to retinoid X receptor α (RXRα), which interacts with thyroid hormone receptor to promote brown adipogenesis and UCP1 induction; CREG1 stimulates UCP1 promoter activity, enhanced by co-expression with thyroid hormone receptors and retinoic acid. In vivo, CREG1 transgenic mice show increased UCP1, elevated energy expenditure after β3-adrenergic stimulation, and resistance to diet-induced obesity. Co-immunoprecipitation (CREG1–RXRα), reporter assay (Ucp1 promoter), transgenic mice, primary BAT cultures, pharmacological stimulation FASEB journal Medium 30917000
2020 CREG1 expression is epigenetically regulated by DNMT3B-mediated promoter hypermethylation; ox-LDL increases DNMT3B expression, methylates the CG site at +201/+202 bp of the CREG promoter, blocks transcription factor GR-α binding, and suppresses CREG expression causing endothelial dysfunction. 5-aza-dC (DNMT inhibitor) restores CREG expression and eNOS/NO pathway activity. DNMT3B overexpression/inhibition, bisulfite sequencing, promoter mutagenesis, ChIP assay, CREG promoter reporter assay Redox biology High 32067910
2020 CREG1 is cleaved by cathepsin B in vitro; cathepsin B overexpression reduces secreted CREG1 abundance while cathepsin B deletion or inhibition increases it, identifying cathepsin B as a negative regulator of secreted CREG1 levels in the tumor microenvironment. In vitro cleavage assay with cathepsin B, conditioned media proteomics from PyMT tumor-macrophage co-cultures, cathepsin B genetic overexpression/deletion Cellular and molecular life sciences Medium 32385587
2021 CREG1 is mainly localized to the endosomal-lysosomal compartment (validated by antibodies in gain/loss-of-function contexts); it promotes macropinocytosis, clathrin-dependent endocytosis, endosomal-lysosomal acidification, and lysosomal biogenesis. CREG1 overexpression enhances autophagy and lysosome-mediated degradation, whereas knockdown/knockout has opposite effects. Immunofluorescence microscopy with validated antibodies, gain- and loss-of-function (KO/KD/OE), acridine orange staining, transferrin uptake assay, LAMP1/cathepsin D functional assays Autophagy High 33966596
2021 CREG1 localizes to mitochondria and is required for mitophagy in skeletal muscle; skeletal muscle-specific creg1 KO mice show impaired exercise endurance, abnormal mitochondrial morphology, elevated PINK1 and PARKIN, and reduced mitochondrial proteins (PTGS2/COX2, COX4I1, TOMM20), indicating accelerated but dysregulated mitophagy. HSPD1/HSP60 (residues 401–573) interacts with CREG1 (residues 130–220) to stabilize CREG1 and is involved in mitophagy regulation. Skeletal muscle-specific Creg1 KO (Creg1;Ckm-Cre), recombinant CREG1 administration, electron microscopy, Western blot, Co-IP (CREG1–HSPD1), C2C12 gain/loss-of-function Autophagy High 33726618
2021 CREG1 inhibits phenotype switching of cardiac fibroblasts to myofibroblasts after MI by suppressing CDC42 expression; recombinant CREG1 protein inhibits αSMA and collagen-1 expression and blocks hypoxia-induced proliferation and migration of cardiac fibroblasts, and this is mediated through inhibition of CDC42. Creg1+/- mice, recombinant CREG1 protein administration, in vitro hypoxia model, Western blot, CDC42 mechanistic experiments Cell death & disease Medium 33824277
2013 CREG1 promotes HUVEC proliferation through the ERK/cyclin E signaling pathway; CREG overexpression increases S/G2 population and cyclin E expression at mRNA and protein level, blocked by ERK inhibition. The pro-proliferative effect is partially mediated by VEGF-induced ERK/cyclin E activation. Adenoviral overexpression, shRNA knockdown, flow cytometry, BrdU incorporation, ERK inhibitor and VEGF neutralizing antibody blocking, RT-PCR, Western blot International journal of molecular sciences Medium 24018888
2016 CREG1 transcription is positively regulated by the transcription factor GATA1 binding to the CREG promoter at -297/-292 bp; deletion mutation of this site reduces CREG transcription by ~83% and abolishes GATA1-mediated activation. GATA1 overexpression upregulates CREG and abrogates high glucose/palmitate-induced endothelial apoptosis. Promoter-reporter assay, ChIP assay, promoter deletion mutagenesis, GATA1 overexpression PloS one Medium 27139506
2023 CREG1 inhibits LAMP2 protein degradation by suppressing FBXO27 E3-ubiquitin ligase expression; LAMP2 overexpression reverses the effect of CREG1 knockdown on cardiomyocyte autophagy inhibition in diabetic cardiomyopathy, defining the CREG1-FBXO27-LAMP2 axis. CREG1 transgenic and cardiac-specific KO mice, palmitate-stimulated NMCMs, Western blot, LAMP2 overexpression rescue, FBXO27 expression analysis Experimental & molecular medicine Medium 37658156
2023 CREG1 directly interacts with MEK1/2 and promotes MEK1/2 phosphorylation, which is required for megakaryocyte maturation and proplatelet formation; Creg1 conditional KO megakaryocytes display impaired actin cytoskeleton (less F-actin), fewer proplatelets, and lower ploidy, resulting in thrombocytopenia. Megakaryocyte/platelet conditional Creg1 KO and transgenic mice, co-immunoprecipitation (CREG1–MEK1/2), Western blot, actin staining, thrombocytopenia model International journal of biological sciences Medium 37496998
2024 CREG1 inhibits ferroptosis in cardiomyocytes by regulating the FBXW7-FOXO1 pathway to suppress PDK4 mRNA and protein expression; PDK4 deficiency reverses the effects of CREG1 knockdown on DOX-induced ferroptosis, placing PDK4 downstream of CREG1-FBXW7-FOXO1. CREG1 transgenic and cardiac-specific KO mice, NMCMs with siRNA/adenovirus, transcriptomics, Western blot, immunoprecipitation Redox biology Medium 39094399
2024 CREG1 deficiency inhibits skeletal muscle satellite cell differentiation and regeneration by promoting C-CBL E3-ubiquitin ligase-mediated K48-linked polyubiquitination of AMPKα1 at K396, leading to AMPKα1 degradation; silencing C-CBL in Creg1 myofibre-KO mice rescues muscle regeneration. Satellite cell-specific Creg1 OE and myofibre-specific Creg1 KO mice, mass spectrometry, RNA sequencing, AAV-shC-CBL silencing rescue, Western blot Journal of cachexia, sarcopenia and muscle Medium 38272853
2024 CREG1 promotes exosome biogenesis and release from bovine placental trophoblast cells by targeting IGF2R; IGF2R knockdown inhibits exosome genesis and blocks CREG1-induced exosome release. CREG1 binds IGF2R which subsequently binds Rab11 to regulate exosomal vesicle formation. Overexpression/knockdown of CREG1 and IGF2R, exosome isolation and characterization, Co-IP (IGF2R–Rab11) International journal of biological macromolecules Medium 38917918
2022 CREG1 stimulates AMPK phosphorylation and glucose uptake in skeletal muscle cells via IGF2R; CREG1-induced AMPKα phosphorylation and 2-deoxyglucose uptake are suppressed by IGF2R knockdown and the AMPK inhibitor Compound C, placing IGF2R upstream of AMPK in CREG1 signaling. C2C12 myotubes, recombinant CREG1 treatment, IGF2R siRNA knockdown, AMPK inhibitor Compound C, Western blot, 2-DG uptake assay Biochemical and biophysical research communications Medium 36528955
2022 CREG1 promotes ESC differentiation into smooth muscle cells via the TGF-β/Smad2/3 signaling pathway; CREG overexpression increases SMC markers and contractile function while CREG KO reduces them; TGF-β-Smad2/3 pathway mediates this effect. ESC CREG OE and KO models, differentiation assay, Western blot, calcium imaging, Smad2/3 pathway analysis Differentiation Medium 35349881
2024 In zebrafish, creg1 deficiency impairs erythroid differentiation and causes excessive apoptosis of erythroid progenitors through reduced activation of the TGF-β/Smad2 signaling pathway; IDE2 (Smad2 pathway agonist) rescues the erythroid defect in creg1-/- mutants. Klf1 is a key downstream target of TGF-β/Smad2 involved in CREG1-mediated erythropoiesis. Zebrafish creg1 knockout, IDE2 pharmacological rescue, Klf1 target analysis, in situ hybridization, flow cytometry Advanced science Medium 38953462
2025 CREG1 promotes lysosomal biogenesis and autophagy in cardiomyocytes; global Creg1 KO mice develop age-associated cardiac hypertrophy, fibrosis, and diastolic dysfunction (~80 weeks). CREG1 localizes to endolysosomal and autophagosomal compartments; its loss impairs autophagy flux and mitophagy due to defective autophagosome membrane expansion and degradation. Global Creg1 KO (full ORF deletion), cardiomyocyte-specific KO and KI mice, electron microscopy, immunofluorescence, CAG-EGFP-RFP-LC3 autophagy reporter, echocardiography bioRxivpreprint Medium 41292877
2025 CREG1 promotes osteogenic differentiation of BMSCs and bone homeostasis via RAB7-mediated regulation of autophagy; RAB7 knockdown inhibits CREG1-induced osteogenic differentiation and autophagy, while RAB7 overexpression restores osteogenic potential suppressed by CREG1 knockdown, placing RAB7 downstream of CREG1. CREG1 and RAB7 overexpression/knockdown in BMSCs, osteogenic differentiation assay, autophagy flux assay, in vivo OVX osteoporosis model Cellular signalling Low 41577020

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 59 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 42 32067910
2021 CREG1 improves the capacity of the skeletal muscle response to exercise endurance via modulation of mitophagy. Autophagy 37 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
2004 CREG, a new regulator of ERK1/2 in cardiac hypertrophy. Journal of hypertension 32 15257182
2023 The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes. Experimental & molecular medicine 31 37658156
2018 The Structure and Biological Function of CREG. Frontiers in cell and developmental biology 27 30416997
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
2024 CREG1 attenuates doxorubicin-induced cardiotoxicity by inhibiting the ferroptosis of cardiomyocytes. Redox biology 20 39094399
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 15 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
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
2014 CREG promotes vasculogenesis by activation of VEGF/PI3K/Akt pathway. Frontiers in bioscience (Landmark edition) 10 24896346
2025 CREG1 attenuates intervertebral disc degeneration by alleviating nucleus pulposus cell pyroptosis via the PINK1/Parkin-related mitophagy pathway. International immunopharmacology 9 39746276
2023 PABPN1 promotes clear cell renal cell carcinoma progression by suppressing the alternative polyadenylation of SGPL1 and CREG1. Carcinogenesis 8 37452741
2022 CREG ameliorates embryonic stem cell differentiation into smooth muscle cells by modulation of TGF-β expression. Differentiation; research in biological diversity 8 35349881
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
2025 IL-33-Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1-IGF2R Axis in Ankylosing Spondylitis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 7 40091508
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 The secreted inhibitor of invasive cell growth CREG1 is negatively regulated by cathepsin proteases. Cellular and molecular life sciences : CMLS 5 32385587
2020 CREG improves cardiac function by regulating cardiomyocytes' autophagy in diabetic myocardial infarction rats. European review for medical and pharmacological sciences 5 33215442
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 1 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