Affinage

TF

Serotransferrin · UniProt P02787

Length
698 aa
Mass
77.1 kDa
Annotated
2026-06-10
100 papers in source corpus 1 papers cited in narrative 1 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 1/1 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Transferrin (TF) binds the transferrin receptor on mammalian cells and mediates receptor-dependent internalization, a property demonstrated functionally by conjugating Tf to a mutant diphtheria toxin (CRM107): the Tf-CRM107 conjugate was cytotoxic at picomolar concentrations against transferrin-receptor-expressing cells, establishing that Tf-receptor binding alone is sufficient to deliver a large protein payload into the cell interior via endocytosis (PMID:14649881). Beyond this ligand-receptor binding and endocytic delivery activity (PMID:14649881), no further mechanistic detail of TF itself has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 2003 Medium

    Established that Tf binding to the transferrin receptor is sufficient to drive efficient endocytic internalization of a bound macromolecular cargo, validating the receptor-ligand axis as a delivery route.

    Evidence In vitro cytotoxicity assay with a Tf-CRM107 (mutant diphtheria toxin) conjugate on receptor-expressing mammalian cells, with confirmation in Phase I/II clinical settings

    PMID:14649881

    Open questions at the time
    • Mechanism inferred from a targeting conjugate rather than direct structural or biochemical reconstitution of native Tf function
    • Iron-binding and iron-delivery activity of TF not directly assayed in this corpus
    • Receptor-binding interface and endocytic trafficking steps not resolved structurally

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TF binds, sequesters, and releases iron, and the structural basis of its interaction with the transferrin receptor, remain uncharacterized in the available corpus.
  • No direct biochemical demonstration of iron binding or release by TF
  • No structural model of the TF-receptor complex in this corpus
  • Endosomal pH-dependent iron unloading mechanism not addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 1

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Human transferrin (Tf) binds the transferrin receptor expressed on mammalian cells and mediates internalization; a conjugate of Tf linked to a mutant diphtheria toxin (CRM107) via a thioester bond exhibited potent cytotoxicity at picomolar concentrations against cells expressing the transferrin receptor, demonstrating that Tf-receptor binding is sufficient to deliver a large protein payload intracellularly. In vitro cytotoxicity assay using Tf-CRM107 conjugate on mammalian cells expressing the transferrin receptor; Phase I/II clinical trials confirming receptor-mediated tumor cell killing Journal of neuro-oncology Medium 14649881

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proceedings of the National Academy of Sciences of the United States of America 400 1311101
2003 Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. Journal of neuro-oncology 240 14649881
2018 REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Annals of the rheumatic diseases 223 30563869
2021 TF-PROTACs Enable Targeted Degradation of Transcription Factors. Journal of the American Chemical Society 196 34100597
2000 COUP-TF orphan nuclear receptors in development and differentiation. Cellular and molecular life sciences : CMLS 160 11078018
1993 COUP-TF acts as a competitive repressor for estrogen receptor-mediated activation of the mouse lactoferrin gene. Molecular and cellular biology 98 8441416
2013 Functional characterization of the alphavirus TF protein. Journal of virology 95 23720714
2004 The COUP-TF nuclear receptors regulate cell migration in the mammalian basal forebrain. Development (Cambridge, England) 94 15548577
1995 Chicken ovalbumin upstream promoter transcription factor (COUP-TF): expression during mouse embryogenesis. The Journal of steroid biochemistry and molecular biology 94 7626501
1994 Developmental regulation of the orphan receptor COUP-TF II gene in spinal motor neurons. Development (Cambridge, England) 92 8119130
2021 UniBind: maps of high-confidence direct TF-DNA interactions across nine species. BMC genomics 75 34174819
1990 COUP-TF gene: a structure unique for the steroid/thyroid receptor superfamily. Nucleic acids research 67 2263450
2008 Dual role of COUP-TF-interacting protein 2 in epidermal homeostasis and permeability barrier formation. The Journal of investigative dermatology 65 19092943
2018 Construction and analysis of mRNA, miRNA, lncRNA, and TF regulatory networks reveal the key genes associated with prostate cancer. PloS one 62 30138363
2019 A map of direct TF-DNA interactions in the human genome. Nucleic acids research 56 30517703
2007 Histone deacetylase inhibitors suppress TF-kappaB-dependent agonist-driven tissue factor expression in endothelial cells and monocytes. The Journal of biological chemistry 55 17675290
2022 TF-DUBTACs Stabilize Tumor Suppressor Transcription Factors. Journal of the American Chemical Society 52 35786952
2017 Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins. Viruses 51 28820485
2016 Identifying Cancer Subtypes from miRNA-TF-mRNA Regulatory Networks and Expression Data. PloS one 46 27035433
2016 Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis simultaneously induced by N-nitrosodiethylamine in mice. Toxicology and applied pharmacology 45 27058323
2004 FVIIa:TF induces cell survival via G12/G13-dependent Jak/STAT activation and BclXL production. Circulation research 43 15016732
1996 Developmental expression and differential regulation by retinoic acid of Xenopus COUP-TF-A and COUP-TF-B. Mechanisms of development 43 8652410
1998 The orphan nuclear receptor, COUP-TF II, inhibits myogenesis by post-transcriptional regulation of MyoD function: COUP-TF II directly interacts with p300 and myoD. Nucleic acids research 42 9826778
2017 Palmitoylation of Sindbis Virus TF Protein Regulates Its Plasma Membrane Localization and Subsequent Incorporation into Virions. Journal of virology 41 27852864
1995 Isolation, characterization, and chromosomal localization of mouse and human COUP-TF I and II genes. Genomics 41 8530078
2018 Fine-Resolution Mapping of TF Binding and Chromatin Interactions. Cell reports 39 29514105
2020 Critical microRNAs and regulatory motifs in cleft palate identified by a conserved miRNA-TF-gene network approach in humans and mice. Briefings in bioinformatics 38 31589286
2012 Anti-Thomsen-Friedenreich-Ag (anti-TF-Ag) potential for cancer therapy. Frontiers in bioscience (Scholar edition) 36 22202095
2001 Physiological function of the orphans GCNF and COUP-TF. Trends in endocrinology and metabolism: TEM 36 11445441
2009 Tf-lipoplex-mediated c-Jun silencing improves neuronal survival following excitotoxic damage in vivo. Journal of controlled release : official journal of the Controlled Release Society 34 19913061
2013 The nuclear receptors COUP-TF: a long-lasting experience in forebrain assembly. Cellular and molecular life sciences : CMLS 32 23525662
2018 Epithelial mesenchymal transition Transcription Factor (TF): The structure, function and microRNA feedback loop. Gene 31 29936265
2014 Eukaryotic and archaeal TBP and TFB/TF(II)B follow different promoter DNA bending pathways. Nucleic acids research 31 24744242
2007 Expression of COUP-TF-interacting protein 2 (CTIP2) in mouse skin during development and in adulthood. Gene expression patterns : GEP 31 17631058
2003 Regulation of differential COUP-TF-coregulator interactions in adrenal cortical steroidogenesis. The Journal of steroid biochemistry and molecular biology 31 12943735
2002 Raf-induced cell cycle progression in human TF-1 hematopoietic cells. Cell cycle (Georgetown, Tex.) 31 12429936
2001 Regulation of laminin and COUP-TF expression in extraembryonic endodermal cells. Mechanisms of development 31 11231078
1995 Orphan receptor COUP-TF I antagonizes retinoic acid-induced neuronal differentiation. Journal of neuroscience research 31 7674376
2014 From miRNA regulation to miRNA-TF co-regulation: computational approaches and challenges. Briefings in bioinformatics 30 25016381
2002 Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in the placenta and myometrium. European journal of obstetrics, gynecology, and reproductive biology 29 12270558
2021 Mitochondria-related core genes and TF-miRNA-hub mrDEGs network in breast cancer. Bioscience reports 27 33439992
2019 Identification of aberrantly expressed lncRNA and the associated TF-mRNA network in hepatocellular carcinoma. Journal of cellular biochemistry 27 31498488
2020 Synthesis of the Thomsen-Friedenreich-antigen (TF-antigen) and binding of Galectin-3 to TF-antigen presenting neo-glycoproteins. Glycoconjugate journal 25 32367478
2014 Integrative identification of deregulated miRNA/TF-mediated gene regulatory loops and networks in prostate cancer. PloS one 25 24968068
1996 Estrogenic effect on the expression of estrogen receptor, COUP-TF, and lactoferrin mRNA in developing mouse tissues. Molecular reproduction and development 25 8873065
2019 Targeting TF-AKT/ERK-EGFR Pathway Suppresses the Growth of Hepatocellular Carcinoma. Frontiers in oncology 23 30931258
2016 mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cells. Thrombosis and haemostasis 23 27808345
2020 Dual threshold optimization and network inference reveal convergent evidence from TF binding locations and TF perturbation responses. Genome research 22 32060051
2016 The role of TF- and Tn-antigens in breast cancer metastasis. Histology and histopathology 22 26758176
2021 Construction of miRNA-mRNA-TF Regulatory Network for Diagnosis of Gastric Cancer. BioMed research international 21 34840985
2020 TF protein of Sindbis virus antagonizes host type I interferon responses in a palmitoylation-dependent manner. Virology 21 32056669
2020 Development, phenotypes of immune cells in BTBR T+Itpr3tf/J mice. Cellular immunology 20 33137646
2018 ELF3 is an antagonist of oncogenic-signalling-induced expression of EMT-TF ZEB1. Cancer biology & therapy 20 30148686
2020 The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus. Cells 19 32093016
1997 Tissue factor (TF) and urokinase plasminogen activator receptor (uPAR) and bleeding complications in leukemic patients. Thrombosis and haemostasis 19 9031451
2021 1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development. Developmental cell 18 34762852
2022 TF-COMB - Discovering grammar of transcription factor binding sites. Computational and structural biotechnology journal 17 35983231
2021 A rapid, sensitive, and specific assay to measure TF activity based on chromogenic determination of thrombin generation. Journal of thrombosis and haemostasis : JTH 17 34822223
2019 Apixaban Suppresses the Release of TF-Positive Microvesicles and Restrains Cancer Cell Proliferation through Directly Inhibiting TF-fVIIa Activity. Thrombosis and haemostasis 17 31266079
2023 Reversal of Cisplatin Resistance in Ovarian Cancer by the Multitargeted Nanodrug Delivery System Tf-Mn-MOF@Nira@CDDP. ACS applied materials & interfaces 16 37218712
2021 Construction of a TF-miRNA-gene feed-forward loop network predicts biomarkers and potential drugs for myasthenia gravis. Scientific reports 16 33510225
2012 Role of thiol pathways in TF procoagulant regulation. Thrombosis research 16 22401798
2004 COUP-TF and transcriptional co-regulators in adrenal steroidogenesis. Endocrine research 16 15666827
1998 Erythropoietin upregulates the expression of its own receptor in TF-1 cell line. Leukemia research 16 9593471
2020 Activation of β1 integrins and caveolin-1 by TF/FVIIa promotes IGF-1R signaling and cell survival. Apoptosis : an international journal on programmed cell death 15 32458278
2019 Abiotic stress induced miRNA-TF-gene regulatory network: A structural perspective. Genomics 15 30876925
2019 MTTFsite: cross-cell type TF binding site prediction by using multi-task learning. Bioinformatics (Oxford, England) 15 31161194
2019 p38/TF/HIF-α Signaling Pathway Participates in the Progression of CIPN in Mice. BioMed research international 15 31380428
2018 Single cell RNA-seq data clustering using TF-IDF based methods. BMC genomics 15 30367575
2022 Paeoniflorin Inhibits ASK1-TF Axis by Up-Regulating SOCS3 to Alleviate Radiation Enteritis. Frontiers in pharmacology 14 35359871
2022 GraphTGI: an attention-based graph embedding model for predicting TF-target gene interactions. Briefings in bioinformatics 14 35511108
2020 Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability. Human molecular genetics 14 31595288
2022 Transcriptome analysis reveals the proline metabolic pathway and its potential regulation TF-hub genes in salt-stressed potato. Frontiers in plant science 13 36325562
2000 Orphan receptors COUP-TF and DAX-1 as targets in disordered CYP17 expression in adrenocortical tumors. Endocrine research 13 11196414
2024 The TF/Nrf2/GSTP1 pathway is involved in stress-induced hepatocellular injury through ferroptosis. Journal of cellular and molecular medicine 12 38890797
2023 TF/PAR2 Signaling Axis Supports the Protumor Effect of Neutrophil Extracellular Traps (NETs) on Human Breast Cancer Cells. Cancers 12 38201433
2013 Meta-analysis on the association between the TF gene rs1049296 and AD. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 12 23968943
2011 Modulation of COUP-TF expression in a cnidarian by ectopic Wnt signalling and allorecognition. PloS one 12 21552541
2008 TF:FVIIa-specific activation of CREB upregulates proapoptotic proteins via protease-activated receptor-2. Journal of thrombosis and haemostasis : JTH 12 18647225
2019 Cross-Cell-Type Prediction of TF-Binding Site by Integrating Convolutional Neural Network and Adversarial Network. International journal of molecular sciences 11 31336830
2019 Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner. Upsala journal of medical sciences 11 31407948
2009 Expression of COUP-TF-interacting protein 2 (CTIP2) in human atopic dermatitis and allergic contact dermatitis skin. Experimental dermatology 11 19366371
2022 Genome-Wide ChIPseq Analysis of AhR, COUP-TF, and HNF4 Enrichment in TCDD-Treated Mouse Liver. International journal of molecular sciences 10 35163483
2022 Towards a better understanding of TF-DNA binding prediction from genomic features. Computers in biology and medicine 10 36057196
2022 Impairments in operant probabilistic reversal learning in BTBR T+tf/J male and female mice. Behavioural brain research 10 36100009
2019 TF-ChIP Method for Tissue-Specific Gene Targets. Frontiers in cellular neuroscience 10 30941015
2008 Notch induces cell cycle arrest and apoptosis in human erythroleukaemic TF-1 cells. Blood cells, molecules & diseases 10 18693120
2001 Adhesion via CD43 induces Syk activation and cell proliferation in TF-1 cells. Biochemical and biophysical research communications 10 11594755
2000 COUP-TF plays a dual role in the regulation of the ovalbumin gene. Biochemistry 10 10913260
2022 Expression patterns of uPAR, TF and EGFR and their potential as targets for molecular imaging in oropharyngeal squamous cell carcinoma. Oncology reports 9 35775375
2022 Exploration of shared TF-miRNA‒mRNA and mRNA-RBP-pseudogene networks in type 2 diabetes mellitus and breast cancer. Frontiers in immunology 9 36131924
2021 Contribution of structural accessibility to the cooperative relationship of TF-lncRNA in myopia. Briefings in bioinformatics 9 33834194
2021 Association of common TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians. Scientific reports 9 33850216
2020 Molecular characterization and expression analysis of Tf_TLR4 and Tf_TRIL in yellow catfish Tachysurus fulvidraco responding to Edwardsiella ictaluri challenge. International journal of biological macromolecules 9 33278446
2019 Activation of TF-Dependent Blood Coagulation Pathway and VEGF-A in Patients with Essential Thrombocythemia. Medicina (Kaunas, Lithuania) 9 30781507
2019 Domains of the TF protein important in regulating its own palmitoylation. Virology 9 30852269
2011 BMP-2 inhibits TF expression in human monocytes by shutting down MAPK signaling and AP-1 transcriptional activity. Thrombosis research 9 22119392
2023 YKL-40 promotes chemokine expression following drug-induced liver injury via TF-PAR1 pathway in mice. Frontiers in pharmacology 8 37693903
2022 An Ensemble Tf-Idf Based Approach to Protein Function Prediction via Sequence Segmentation. IEEE/ACM transactions on computational biology and bioinformatics 8 34185646
2022 Identification of functional TF-miRNA-hub gene regulatory network associated with ovarian endometriosis. Frontiers in genetics 8 36212136

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