Affinage

P4HB

Protein disulfide-isomerase · UniProt P07237

Length
508 aa
Mass
57.1 kDa
Annotated
2026-06-10
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P4HB encodes a multifunctional ER-resident polypeptide that is simultaneously the beta-subunit of the prolyl 4-hydroxylase alpha2beta2 tetramer and the enzyme protein disulfide isomerase (PDI/PDIA1), thereby coupling collagen prolyl hydroxylation with oxidative protein folding (PMID:1647289). Through its disulfide isomerase activity it governs the maturation of multiple secretory clients: it is required for proinsulin disulfide maturation in pancreatic beta cells, where its loss elevates the proinsulin/insulin ratio and produces disulfide-linked high-molecular-weight proinsulin aggregates (PMID:31184304), and it supports hepatic VLDL assembly by chaperoning APOB and enabling MTTP synthesis, with catalytic activity being essential for these functions (PMID:38211723). Its expression is wired to the unfolded protein response: the ER stress sensor IRE1 transcriptionally induces P4HB to drive collagen maturation and secretion (PMID:37205565). A heterozygous p.Tyr393Cys mutation in the C-terminal disulfide isomerase domain abolishes isomerase activity and causes Cole-Carpenter syndrome, a severe bone fragility/osteogenesis imperfecta disorder, acting through disrupted ECM organization rather than a defect in collagen type I secretion per se (PMID:25683117, PMID:29263160). P4HB protein abundance and activity are tuned by post-translational modification, including stabilizing UFMylation whose loss triggers proteasomal degradation, oxidative and ER stress (PMID:35753586). Beyond folding, P4HB orchestrates redox signaling—balancing NOX1/NOX4 to control vascular smooth muscle phenotype switching (PMID:33227407)—and in cancer it promotes malignant phenotypes through MAPK signaling (PMID:29069756), ROS/STAT3 signaling (PMID:30431122), GRP78 downregulation with EMT (PMID:28052026), and secreted P4HB that activates fibroblasts via beta-catenin to drive chemoresistance (PMID:38100120).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1991 High

    Established the dual molecular identity of P4HB, showing one gene product serves both as the prolyl 4-hydroxylase beta-subunit and as protein disulfide isomerase, defining its place in collagen biosynthesis and oxidative folding.

    Evidence In situ hybridization and Southern blot of chromosome-transfer transfectants mapping the gene and establishing dual function

    PMID:1647289

    Open questions at the time
    • Did not resolve how the two catalytic roles are partitioned in vivo
    • No structural model of the alpha2beta2 tetramer provided
  2. 2013 Medium

    Linked P4HB activity to chemoresistance, showing its inhibition sensitizes resistant tumor cells via the PERK arm of the ER stress response.

    Evidence RNAi and bacitracin inhibition with PERK pathway analysis in temozolomide-resistant glioblastoma, validated in xenografts

    PMID:23444257

    Open questions at the time
    • Bacitracin is not P4HB-specific
    • Direct catalytic dependence not dissected
  3. 2015 High

    Demonstrated that a specific P4HB mutation causes human disease by impairing disulfide isomerase activity, tying enzymatic loss-of-function to a Mendelian bone fragility syndrome.

    Evidence Whole-exome sequencing, in vitro isomerase assay, and ER stress analysis of patient fibroblasts for p.Tyr393Cys

    PMID:25683117

    Open questions at the time
    • Normal collagen I secretion left the bone phenotype mechanism unresolved
    • Heterozygous mechanism (dominant-negative vs haploinsufficiency) not defined
  4. 2017 Medium

    Refined the disease mechanism, indicating P4HB perturbation disrupts ECM organization and assembly rather than collagen type I secretion itself.

    Evidence Collagen and electron microscopy analysis of patient fibroblasts with exome sequencing

    PMID:29263160

    Open questions at the time
    • Molecular basis of ECM disorganization not identified
    • Single-lab fibroblast study
  5. 2017 Medium

    Placed P4HB's oncogenic activity downstream of defined signaling, implicating MAPK and GRP78/EMT axes in tumor promotion.

    Evidence Gain/loss-of-function with MAPK pathway analysis in glioma and GRP78 modulation in HCC, both with in vivo validation

    PMID:28052026 PMID:29069756

    Open questions at the time
    • How catalytic isomerase function connects to MAPK/GRP78 not established
    • Direct substrates in these pathways unknown
  6. 2018 Medium

    Defined a ROS-STAT3 axis downstream of P4HB, showing its knockdown drives apoptosis through ROS accumulation and STAT3 inactivation.

    Evidence siRNA knockdown with ROS measurement, STAT3 phosphorylation, and ROS-inhibitor rescue in colon cancer cells

    PMID:30431122

    Open questions at the time
    • Source of ROS upon P4HB loss not identified
    • Single-lab in vitro study
  7. 2019 High

    Established a physiological catalytic role in proinsulin folding, showing P4HB is required for proinsulin disulfide maturation and beta cell function.

    Evidence Beta cell-specific Pdia1 knockout mice with glucose tolerance, proinsulin/insulin ratio, and ultrastructural analysis

    PMID:31184304

    Open questions at the time
    • Whether PDIA1 acts directly on proinsulin disulfides or via partner chaperones not resolved
    • Specific disulfide bonds catalyzed not mapped
  8. 2020 High

    Revealed a redox-signaling role beyond folding, with PDIA1 acting as master organizer of the NOX1/NOX4 balance to control vascular smooth muscle phenotype switching.

    Evidence Inducible overexpression, siRNA, transgenic mice, and in vivo injury model with NOX activity and myocardin readouts

    PMID:33227407

    Open questions at the time
    • Molecular mechanism by which PDIA1 sets NOX1/NOX4 balance not defined
    • Direct interaction with NOX enzymes not shown
  9. 2020 Medium

    Identified P4HB as a regulator of IRF1 stability, controlling melanogenesis and skin inflammation through ubiquitin-dependent degradation of IRF1.

    Evidence SPR binding, Co-IP, pull-down, PLA, and luciferase assays with the inhibitor salidroside

    PMID:33042273

    Open questions at the time
    • How P4HB mechanistically promotes IRF1 ubiquitination unclear
    • Single-lab study
  10. 2021 Medium

    Extended P4HB function to extracellular and cancer-cachexia contexts, showing secreted/EV P4HB and direct partners drive muscle apoptosis and tumor aggression.

    Evidence EV isolation with PHGDH/Bcl-2 pathway analysis in ESCC cachexia, Co-IP with COL10A1 in breast cancer, and biomarker proteomics in T1D islets

    PMID:33637669 PMID:33732415 PMID:36463755

    Open questions at the time
    • How an ER-resident protein is secreted and functions extracellularly not mechanistically resolved
    • COL10A1 interaction rests on a single Co-IP with functional rescue
    • T1D data are correlative biomarker findings without direct mechanism
  11. 2022 Medium

    Showed P4HB stability is post-translationally controlled by UFMylation, linking this modification to redox and ER homeostasis.

    Evidence UFMylation-defective P4HB cell line with proteasome rescue, mitochondrial, ROS, and ER stress assays in HepG2

    PMID:35753586

    Open questions at the time
    • UFMylated lysine residues not individually mapped to function
    • Ligase/machinery directing P4HB UFMylation not identified
  12. 2022 Medium

    Identified P4HB as the molecular target of disulfide-bond-disrupting agents, connecting its mixed-disulfide client interactions to death-receptor oligomerization in cancer.

    Evidence Affinity purification with biotinylated DDAs, shRNA knockdown, and mixed disulfide bond analysis in breast cancer cells

    PMID:35247515

    Open questions at the time
    • Full client repertoire forming mixed disulfides not enumerated
    • Single-lab characterization
  13. 2023 Medium

    Wired P4HB expression to the unfolded protein response, showing IRE1 transcriptionally induces P4HB to enable collagen maturation and secretion.

    Evidence IRE1 genetic ablation with P4HB overexpression rescue in liver fibrosis models (preprint)

    PMID:37205565

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Transcription factor link between IRE1 and the P4HB promoter not detailed
  14. 2023 Medium

    Defined P4HB as a secreted driver of stromal activation, showing ARID1A loss elevates secreted P4HB that activates fibroblasts via beta-catenin to promote chemoresistance.

    Evidence ARID1A knockdown, conditioned media, antibody neutralization, and PDX models in lung cancer

    PMID:38100120

    Open questions at the time
    • Fibroblast receptor for secreted P4HB not identified
    • Single-lab study
  15. 2024 High

    Established an essential catalytic role in hepatic lipoprotein metabolism, with P4HB chaperoning APOB and enabling MTTP synthesis to support VLDL secretion.

    Evidence Hepatocyte-specific Pdia1 knockout, Co-IP with APOB, translational analysis of MTTP, and catalytic-mutant complementation

    PMID:38211723

    Open questions at the time
    • Mechanism by which P4HB controls MTTP translation specifically unresolved
    • Chaperone vs catalytic contributions to APOB binding not fully separated
  16. 2024 Medium

    Added new layers of post-translational and interaction-based regulation, identifying K311 lactylation and a PRMT1 interaction modulating TGFbeta/SMAD3-driven fibrosis.

    Evidence 4D lactylation proteomics and docking for K311; Co-IP and overexpression epistasis for PRMT1 in renal tubular cells

    PMID:39251943 PMID:39494721

    Open questions at the time
    • Functional consequence of K311 lactylation on enzymatic activity not measured
    • PRMT1 interaction rests on single-lab Co-IP and rescue

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ER-resident isomerase coordinates its catalytic folding functions with its diverse cytosolic, extracellular, and signaling roles, and how its many post-translational modifications integrate to regulate these activities, remains unresolved.
  • No unified structural/mechanistic model linking folding catalysis to signaling outputs
  • Secretion route for an ER-resident protein unexplained
  • Substrate-level specificity across tissues not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 5 GO:0016491 oxidoreductase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005576 extracellular region 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-1430728 Metabolism 1
Partners
APOBCOL10A1IRF1MTTPPRMT1
Complex memberships
prolyl 4-hydroxylase alpha2beta2 tetramer

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 A heterozygous missense mutation in P4HB (p.Tyr393Cys) located in the C-terminal disulfide isomerase domain of PDI sterically close to the enzymatic center impairs disulfide isomerase activity in vitro and causes Cole-Carpenter syndrome, a severe bone fragility disorder. Skin fibroblasts showed increased ER stress, but collagen type I secretion rate appeared normal. Whole-exome sequencing, in vitro disulfide isomerase activity assay, ER stress analysis in patient skin fibroblasts American journal of human genetics High 25683117
2019 PDIA1/P4HB is required for efficient proinsulin disulfide maturation in pancreatic β cells. β cell-specific Pdia1 deletion in mice exacerbated glucose intolerance, increased the proinsulin/insulin ratio, caused accumulation of disulfide-linked high-molecular-weight proinsulin complexes, and produced ER vesiculation, mitochondrial swelling, and nuclear condensation. Conditional β cell-specific Pdia1 knockout mice, glucose tolerance tests, proinsulin/insulin ratio measurement in serum and islets, ultrastructural analysis, oxidative stress assays eLife High 31184304
2024 PDIA1 plays indispensable roles in APOB folding and MTTP synthesis/function to support VLDL assembly and secretion in hepatocytes. Hepatocyte-specific Pdia1 deletion inhibited MTTP expression at the translational level (not mRNA or protein stability), dramatically reduced VLDL production, and caused severe hepatic steatosis and hypolipidemia. PDIA1 interacts with APOB in an MTTP-independent manner via its chaperone function. Catalytically inactivated PDIA1 mutant failed to rescue these phenotypes. Conditional hepatocyte-specific Pdia1 knockout mice, lipoprotein secretion assays, mRNA/protein stability analysis, Co-IP between PDIA1 and APOB, catalytic mutant complementation Molecular metabolism High 38211723
2022 P4HB is a substrate for UFMylation at three lysine residues (mono-UFMylation). UFMylation deficiency promotes P4HB protein degradation via the ubiquitin-proteasome pathway, leading to mitochondrial function damage, oxidative stress, and ER stress in HepG2 cells. Stable cell line with UFMylation-defective P4HB, proteasome inhibitor rescue experiments, mitochondrial function assays, ROS measurement, ER stress markers Free radical biology & medicine Medium 35753586
2024 P4HB is lactylated at lysine K311; aloe emodin inhibits binding of lactate to the K311 site of P4HB. P4HB lactylation was identified as a novel post-translational modification relevant to radiation-induced heart disease. 4D label-free lactylation omics, cross differential omics, molecular docking, identification of K311 as the lactylation site Advanced science Medium 39494721
2013 P4HB inhibition (by RNAi knockdown or bacitracin) sensitizes temozolomide-resistant glioblastoma cells to TMZ through the PERK arm of the endoplasmic reticulum stress response. P4HB overexpression conferred TMZ resistance in sensitive cells. RNAi knockdown, pharmacological inhibition (bacitracin), in vitro and in vivo xenograft models, ER stress pathway analysis (PERK arm) Neuro-oncology Medium 23444257
1991 P4HB encodes a multifunctional polypeptide that serves as the beta-subunit of the prolyl 4-hydroxylase alpha2beta2 tetramer (which catalyzes 4-hydroxyproline formation in collagens) and is identical to the enzyme protein disulfide isomerase. The gene was mapped to chromosome 17q25. In situ hybridization, Southern blot analysis of chromosome-mediated gene transfer transfectant panel Cytogenetics and cell genetics High 1647289
2017 P4HB (PDI) in its tetrameric form catalyzes hydroxylation of proline residues within X-Pro-Gly repeats in the procollagen helical domain. The recurrent mutation p.Tyr393Cys in the C-terminal reactive centre interferes with disulfide isomerase function of PDI. Fibroblast analysis suggests P4HB perturbation disrupts ECM organization and assembly rather than collagen type I secretion per se. Collagen analysis in cultured fibroblasts, electron microscopy, exome sequencing, clinical phenotyping Journal of medical genetics Medium 29263160
2020 PDIA1 acts as master organizer of NOX1/NOX4 balance in vascular smooth muscle cells (VSMCs). Early PDIA1 overexpression increased NOX1 expression, H2O2 levels, and spontaneous VSMC migration; sustained overexpression also increased NOX4 and switched VSMC phenotype to differentiation. PDIA1 knockdown decreased nuclear myocardin and increased PCNA expression. Both NOX1 and H2O2 were necessary for PDIA1-induced VSMC differentiation. In vivo, TgPDIA1 carotids showed decreased NOX1 and enhanced NOX4/calponin, indicating overdifferentiation. Inducible PDIA1 overexpression in VSMCs, siRNA knockdown, transgenic PDIA1-overexpressing mice (TgPDIA1), rabbit overdistension injury model, NOX1/NOX4 expression and activity assays, nuclear myocardin imaging Free radical biology & medicine High 33227407
2022 PDIA1 (P4HB) is a target protein of Disulfide bond Disrupting Agents (DDAs). Affinity purification with biotinylated DDAs identified PDIA1 as a DDA-binding protein. DDA treatment of breast cancer cells disrupts PDIA1 mixed disulfide bonds with client proteins, contributing to DR4/DR5 oligomerization and cancer cell death. Affinity purification with biotinylated-DDAs, shRNA knockdown, mixed disulfide bond analysis Cancer letters Medium 35247515
2021 P4HB is secreted in extracellular vesicles from esophageal squamous cell carcinoma cells and promotes apoptosis of skeletal muscle cells by activating the ubiquitin-dependent proteolytic pathway and regulating the stability of PHGDH and subsequent antiapoptotic protein Bcl-2, contributing to cancer cachexia. ESCC-induced cachexia mouse model, EV isolation, P4HB inhibitor (CCF642) treatment, apoptosis assays, PHGDH/Bcl-2/caspase-3 pathway analysis Journal of extracellular vesicles Medium 33732415
2020 SAL (salidroside) inhibits skin inflammation and melanogenesis by targeting P4HB (confirmed by molecular docking and Biacore binding). P4HB mediates ubiquitination-dependent degradation of IRF1; inhibition of P4HB by SAL prevents IRF1 ubiquitin degradation. IRF1 and USF1 form a transcription complex that regulates tyrosinase (TYR) mRNA expression. Molecular docking, Biacore surface plasmon resonance, Co-IP, pull-down, proximity ligation assay, luciferase reporter assay, immunofluorescence, Western blot Theranostics Medium 33042273
2023 The ER stress sensor IRE1 regulates collagen secretion through transcriptional induction of P4HB/PDIA1, which is required for collagen maturation. Genetic ablation of IRE1 reduced P4HB expression, caused collagen retention at the ER and altered secretion, and diminished collagen deposition in liver fibrosis models. P4HB overexpression rescued collagen secretion in IRE1-deficient cells. IRE1 genetic ablation, carbon tetrachloride and high-fat diet liver fibrosis models, proteomic and transcriptomic profiling, P4HB overexpression rescue, collagen retention/secretion assays bioRxivpreprint Medium 37205565
2017 P4HB promotes malignant glioma phenotypes (proliferation, invasion, migration, angiogenesis) via the MAPK signaling pathway. Genetic and pharmacologic inhibition of P4HB suppressed MAPK expression and downstream angiogenic/invasive targets. P4HB overexpression and knockdown, in vitro proliferation/invasion/migration/angiogenesis assays, in vivo tumor growth, MAPK pathway analysis Oncotarget Medium 29069756
2024 P4HB interacts with PRMT1 (confirmed by immunoprecipitation), and this interaction mediates P4HB's regulation of the TGFβ/SMAD3 signaling pathway in high glucose-induced renal tubular epithelial cells. Silencing P4HB inhibited EMT and fibrosis; overexpression of PRMT1 reversed P4HB knockdown effects on EMT, fibrosis, and TGFβ/SMAD3 signaling. siRNA knockdown, overexpression vectors, immunoprecipitation (P4HB-PRMT1 interaction), Western blot, immunofluorescence, ROS assay BMC nephrology Medium 39251943
2021 COL10A1 directly interacts with P4HB (confirmed by Co-IP). P4HB is required for COL10A1-mediated promotion of breast cancer cell proliferation, migration, and invasion, as P4HB knockdown abrogated the promoting effects of COL10A1 overexpression. Co-immunoprecipitation, siRNA knockdown of P4HB, CCK-8 proliferation assay, wound healing and transwell migration/invasion assays Medical science monitor Low 33637669
2017 P4HB promotes HCC tumorigenesis through downregulation of GRP78 and subsequent upregulation of epithelial-to-mesenchymal transition (EMT). GRP78 overexpression antagonized the oncogenic effects of P4HB overexpression in HCC cells. P4HB overexpression and silencing, in vitro growth/migration/invasion/EMT assays, in vivo tumor xenografts, GRP78 modulation Oncotarget Medium 28052026
2018 P4HB knockdown in HT29 colon cancer cells induces apoptosis through accumulation of reactive oxygen species (ROS) and subsequent inactivation of STAT3 signaling. Inhibiting ROS accumulation abrogated the increased apoptosis, and decreased ROS effectively antagonized P4HB knockdown effects on STAT3 inactivation. siRNA knockdown, ROS measurement, STAT3 phosphorylation assay, apoptosis assay, ROS inhibitor rescue Molecular medicine reports Medium 30431122
2023 ARID1A depletion in lung cancer cells augments P4HB expression and secretion; secreted P4HB induces activation of lung fibroblasts through the β-catenin signaling pathway. P4HB-activated fibroblasts promote proliferation, invasion, and chemoresistance of lung cancer cells. Antibody-based P4HB neutralization hampered tumor growth and increased cisplatin efficacy in PDX models. siRNA knockdown of ARID1A, conditioned media experiments, antibody neutralization, β-catenin pathway analysis, PDX mouse models Cancer science Medium 38100120
2021 PDIA1 is upregulated in NOD mouse islets and pancreatic sections from humans with autoantibody positivity or T1D. PDIA1 plasma levels are increased in pre-diabetic NOD mice and in children with recent-onset T1D, suggesting PDIA1 as a biomarker of β cell stress. Data independent acquisition-mass spectrometry on longitudinally collected islets from NOD mice, immunohistochemistry of human pancreatic sections, ELISA for plasma PDIA1 EBioMedicine Low 36463755

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 1433 10622253
2001 Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 328 11559724
2005 The GIT-associated kinase PAK targets to the centrosome and regulates Aurora-A. Molecular cell 209 16246726
2006 The multifunctional GIT family of proteins. Journal of cell science 196 16598076
2005 IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells. Cytokine 135 15749028
2000 GIT proteins, A novel family of phosphatidylinositol 3,4, 5-trisphosphate-stimulated GTPase-activating proteins for ARF6. The Journal of biological chemistry 134 10788515
2003 Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF. The Journal of cell biology 133 14597771
1993 Relatedness of an RNA-binding motif in human immunodeficiency virus type 1 TAR RNA-binding protein TRBP to human P1/dsI kinase and Drosophila staufen. Molecular and cellular biology 126 8455607
2007 Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 122 17928638
2003 Involvement of site-specific FAK phosphorylation in sphingosine-1 phosphate- and thrombin-induced focal adhesion remodeling: role of Src and GIT. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 118 14656986
2000 The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing. The Journal of biological chemistry 118 10896954
2002 The GIT family of proteins forms multimers and associates with the presynaptic cytomatrix protein Piccolo. The Journal of biological chemistry 115 12473661
2016 Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT-PIX complexes. Journal of cell science 97 27182061
2004 The GIT/PIX complex: an oligomeric assembly of GIT family ARF GTPase-activating proteins and PIX family Rac1/Cdc42 guanine nucleotide exchange factors. Cellular signalling 94 15212761
2015 Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. American journal of human genetics 78 25683117
2013 Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways. Neuro-oncology 76 23444257
1993 Six git genes encode a glucose-induced adenylate cyclase activation pathway in the fission yeast Schizosaccharomyces pombe. Journal of cell science 74 8227198
2019 PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity. eLife 73 31184304
2008 The PIX-GIT complex: a G protein signaling cassette in control of cell shape. Seminars in cell & developmental biology 71 18299239
2017 P4HB and PDIA3 are associated with tumor progression and therapeutic outcome of diffuse gliomas. Oncology reports 61 29207176
2004 Mitochondrial ROS generation following acetylcholine-induced EGF receptor transactivation requires metalloproteinase cleavage of proHB-EGF. Journal of molecular and cellular cardiology 60 15010282
2001 BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation. The Journal of biological chemistry 57 11340068
2008 A RAC/CDC-42-independent GIT/PIX/PAK signaling pathway mediates cell migration in C. elegans. PLoS genetics 52 19023419
2014 RhoJ interacts with the GIT-PIX complex and regulates focal adhesion disassembly. Journal of cell science 50 24928894
2008 Structures of dimeric GIT1 and trimeric beta-PIX and implications for GIT-PIX complex assembly. Journal of molecular biology 50 19136011
2021 Extracellular vesicles derived from oesophageal cancer containing P4HB promote muscle wasting via regulating PHGDH/Bcl-2/caspase-3 pathway. Journal of extracellular vesicles 49 33732415
2020 GIT/PIX Condensates Are Modular and Ideal for Distinct Compartmentalized Cell Signaling. Molecular cell 49 32780989
2003 Leucine-zipper-mediated homo- and hetero-dimerization of GIT family p95-ARF GTPase-activating protein, PIX-, paxillin-interacting proteins 1 and 2. The Biochemical journal 47 12611588
2019 P4HB, a Novel Hypoxia Target Gene Related to Gastric Cancer Invasion and Metastasis. BioMed research international 45 31467922
2012 Demonstration of DSI-semen--A novel DNA methylation-based forensic semen identification assay. Forensic science international. Genetics 45 22944353
2020 Salidroside can target both P4HB-mediated inflammation and melanogenesis of the skin. Theranostics 44 33042273
2017 P4HB promotes HCC tumorigenesis through downregulation of GRP78 and subsequent upregulation of epithelial-to-mesenchymal transition. Oncotarget 44 28052026
2011 Sorting nexin 27 protein regulates trafficking of a p21-activated kinase (PAK) interacting exchange factor (β-Pix)-G protein-coupled receptor kinase interacting protein (GIT) complex via a PDZ domain interaction. The Journal of biological chemistry 40 21926430
2022 P4HB UFMylation regulates mitochondrial function and oxidative stress. Free radical biology & medicine 39 35753586
2003 Functional significance of cannabinoid-mediated, depolarization-induced suppression of inhibition (DSI) in the hippocampus. Journal of neurophysiology 39 12649318
2001 Identification of serum factor inducing ectodomain shedding of proHB-EGF and sStudies of noncleavable mutants of proHB-EGF. Biochemical and biophysical research communications 38 11350072
2013 From the gastrointestinal tract (GIT) to the kidneys: live bacterial cultures (probiotics) mediating reductions of uremic toxin levels via free radical signaling. Toxins 37 24212182
2014 A presynaptic role for the cytomatrix protein GIT in synaptic vesicle recycling. Cell reports 36 24882013
2020 Targeted Inhibition of P4HB Promotes Cell Sensitivity to Gemcitabine in Urothelial Carcinoma of the Bladder. OncoTargets and therapy 34 33061438
2015 Presynaptic Deletion of GIT Proteins Results in Increased Synaptic Strength at a Mammalian Central Synapse. Neuron 34 26637799
1987 Dsi-1, a region with frequent proviral insertions in Moloney murine leukemia virus-induced rat thymomas. Journal of virology 34 3029411
2018 P4HB knockdown induces human HT29 colon cancer cell apoptosis through the generation of reactive oxygen species and inactivation of STAT3 signaling. Molecular medicine reports 33 30431122
2020 P4HB modulates epithelial-mesenchymal transition and the β-catenin/Snail pathway influencing chemoresistance in liver cancer cells. Oncology letters 32 32565952
1979 Tube leukocyte adherence inhibition (LAI) assay in gastrointestinal (GIT) cancer. Cancer 32 371789
2023 Comparing the diagnostic performance of QuantiFERON-TB Gold Plus with QFT-GIT, T-SPOT.TB and TST: a systematic review and meta-analysis. BMC infectious diseases 31 36670347
2002 Presynaptic factors in the regulation of DSI expression in hippocampus. Neuropharmacology 31 12367601
2021 Collagen Type X Alpha 1 (COL10A1) Contributes to Cell Proliferation, Migration, and Invasion by Targeting Prolyl 4-Hydroxylase Beta Polypeptide (P4HB) in Breast Cancer. Medical science monitor : international medical journal of experimental and clinical research 30 33637669
2020 Improving access to and effectiveness of mental health care for personality disorders: the guideline-informed treatment for personality disorders (GIT-PD) initiative in the Netherlands. Borderline personality disorder and emotion dysregulation 30 32789019
1999 Evidence for endogenous excitatory amino acids as mediators in DSI of GABA(A)ergic transmission in hippocampal CA1. Journal of neurophysiology 30 10561426
2024 Aloe Emodin Alleviates Radiation-Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 27 39494721
2014 The GTPase regulatory proteins Pix and Git control tissue growth via the Hippo pathway. Current biology : CB 27 25484297
2008 Suppression of proHB-EGF carboxy-terminal fragment nuclear translocation: a new molecular target therapy for gastric cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 26 18559618
2015 MiR-491 attenuates cancer stem cells-like properties of hepatocellular carcinoma by inhibition of GIT-1/NF-κB-mediated EMT. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 26188902
2013 Poly(4-hydroxybutyrate) (P4HB) production in recombinant Escherichia coli: P4HB synthesis is uncoupled with cell growth. Microbial cell factories 25 24325175
2022 In-Silico Characterization of Estrogen Reactivating β-Glucuronidase Enzyme in GIT Associated Microbiota of Normal Human and Breast Cancer Patients. Genes 24 36140713
2012 Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding. Journal of neuroinflammation 24 22747893
2010 Cadherins and Pak1 control contact inhibition of proliferation by Pak1-betaPIX-GIT complex-dependent regulation of cell-matrix signaling. Molecular and cellular biology 24 20154149
2010 TGFβ induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells. Biochemical and biophysical research communications 24 20934403
1999 Coexpression of CD9 augments the ability of membrane-bound heparin-binding epidermal growth factor-like growth factor (proHB-EGF) to preserve renal epithelial cell viability. Kidney international 24 9893115
1987 A great improvement of fusion efficiency in mouse B cell hybridoma production by use of the new culture medium, GIT. The Tohoku journal of experimental medicine 23 3313808
2017 Endoplasmic reticulum chaperone prolyl 4-hydroxylase, beta polypeptide (P4HB) promotes malignant phenotypes in glioma via MAPK signaling. Oncotarget 22 29069756
2008 Novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide (GIT-27NO) induces p53 mediated apoptosis in human A375 melanoma cells. Nitric oxide : biology and chemistry 22 18460348
2019 In-vitro GIT Tolerance of Microencapsulated Bifidobacterium bifidum ATCC 35914 Using Polysaccharide-Protein Matrix. Probiotics and antimicrobial proteins 20 29532415
2019 NOVEL MUTATIONS IN THE WNT1, TMEM38B, P4HB, AND PLS3 GENES IN FOUR UNRELATED CHINESE FAMILIES WITH OSTEOGENESIS IMPERFECTA. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 20 30913006
2014 Improved productivity of poly (4-hydroxybutyrate) (P4HB) in recombinant Escherichia coli using glycerol as the growth substrate with fed-batch culture. Microbial cell factories 20 25176327
2013 Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells. PloS one 20 23451083
2022 Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death. Cancer letters 19 35247515
2022 Adhesion properties of cell surface proteins in Lactobacillus strains in the GIT environment. Food & function 18 35226005
2021 Injectable Cell- and Growth Factor-Free Poly(4-hydroxybutyrate) (P4HB) Microspheres with Open Porous Structures and Great Efficiency of Promoting Bone Regeneration. ACS applied bio materials 18 35006855
2020 Dsi-RNA knockdown of genes regulated by Foxo reduces glycogen and lipid accumulations in diapausing Culex pipiens. Scientific reports 18 33057122
2020 PDIA1 acts as master organizer of NOX1/NOX4 balance and phenotype response in vascular smooth muscle. Free radical biology & medicine 18 33227407
2010 The impact of asthma on the gastrointestinal tract (GIT). Journal of asthma and allergy 18 21437046
2017 P4HB recurrent missense mutation causing Cole-Carpenter syndrome. Journal of medical genetics 17 29263160
2015 Enterococcus mundtii ST4SA and Lactobacillus plantarum 423 excludes Listeria monocytogenes from the GIT, as shown by bioluminescent studies in mice. Beneficial microbes 17 26689230
2022 A discovery-based proteomics approach identifies protein disulphide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes. EBioMedicine 16 36463755
2019 A novel missense mutation in P4HB causes mild osteogenesis imperfecta. Bioscience reports 16 30948499
2013 Lymphocyte subpopulations in active tuberculosis: association with disease severity and the QFT-GIT assay. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 16 23676170
1991 Regional assignment of the human gene coding for a multifunctional polypeptide (P4HB) acting as the beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide isomerase to 17q25. Cytogenetics and cell genetics 16 1647289
2021 Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma. Cancers 15 34071205
2021 Role of Bacteria in the Incidence of Common GIT Cancers: The Dialectical Role of Integrated Bacterial DNA in Human Carcinogenesis. Infection and drug resistance 15 34103947
2023 ARID1A loss induces P4HB to activate fibroblasts to support lung cancer cell growth, invasion, and chemoresistance. Cancer science 14 38100120
2015 Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance. Journal of inorganic biochemistry 14 26364260
2007 Lack of depolarization-induced suppression of inhibition (DSI) in layer 2/3 interneurons that receive cannabinoid-sensitive inhibitory inputs. Journal of neurophysiology 14 17881480
2012 The adaptor protein and Arf GTPase-activating protein Cat-1/Git-1 is required for cellular transformation. The Journal of biological chemistry 13 22807447
2012 A validation study of the Nucleix DSI-Semen kit--a methylation-based assay for semen identification. International journal of legal medicine 13 22895803
1988 Highly efficient procedure for production of human monoclonal antibodies: establishment of hybrids between Epstein-Barr virus-transformed B lymphocytes and heteromyeloma cells by use of GIT culture medium. The Tohoku journal of experimental medicine 13 2847359
2023 Circular RNA P4HB promotes glycolysis and tumor progression by binding with PKM2 in lung adenocarcinoma. Respiratory research 12 37880717
2017 Cole-Carpenter syndrome-1 with a de novo heterozygous deletion in the P4HB gene in a Chinese girl: A case report. Medicine 12 29384951
2010 The GIT-PIX complexes regulate the chemotactic response of rat basophilic leukaemia cells. Biology of the cell 12 19912111
2024 P4HB regulates the TGFβ/SMAD3 signaling pathway through PRMT1 to participate in high glucose-induced epithelial-mesenchymal transition and fibrosis of renal tubular epithelial cells. BMC nephrology 11 39251943
2014 Isolation and screening of probiotic candidates from marron, Cherax cainii (Austin, 2002) gastrointestinal tract (GIT) and commercial probiotic products for the use in marron culture. Journal of fish diseases 11 24917311
2011 Engineering of living autologous human umbilical cord cell-based septal occluder membranes using composite PGA-P4HB matrices. Biomaterials 11 21978890
2000 Heterosynaptic expression of depolarization-induced suppression of inhibition (DSI) in rat hippocampal cultures. Neuroscience research 11 10678533
2022 Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein-protein interaction inhibitor. Nature communications 10 36418900
2013 Two thioredoxin-superfamily members from sea bass (Dicentrarchus labrax, L.): characterization of PDI (PDIA1) and ERp57 (PDIA3). Fish & shellfish immunology 10 23880452
2009 The novel NO-donating compound GIT-27NO inhibits in vivo growth of human prostate cancer cells and prevents murine immunoinflammatory hepatitis. European journal of pharmacology 10 19446546
2024 Conditional hepatocyte ablation of PDIA1 uncovers indispensable roles in both APOB and MTTP folding to support VLDL secretion. Molecular metabolism 9 38211723
2023 The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis. bioRxiv : the preprint server for biology 9 37205565
2019 The dPix-Git complex is essential to coordinate epithelial morphogenesis and regulate myosin during Drosophila egg chamber development. PLoS genetics 9 31116733
2013 Identification of the cancer cell proliferation and survival functions of proHB-EGF by using an anti-HB-EGF antibody. PloS one 9 23349913

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