Affinage

ID2

DNA-binding protein inhibitor ID-2 · UniProt Q02363

Length
134 aa
Mass
14.9 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ID2 is a helix-loop-helix (HLH) protein that lacks a basic DNA-binding region and acts as a dominant-negative regulator of the proliferation-versus-differentiation decision across neural, hematopoietic, epithelial, and immune lineages (PMID:1922066, PMID:11034201). Its core biochemical activity is heterodimerization with and sequestration of class I bHLH E-proteins (E2A/E47, E12) and tissue-specific bHLH factors such as NeuroD/BETA2, thereby preventing their binding to E-box target promoters (PMID:1922066, PMID:12526101, PMID:16547003). Through this E-protein titration ID2 derepresses or represses defined target genes to drive cell-cycle entry and lineage choice: it blocks E47-driven activation of the CDK inhibitors p57Kip2 and p27KIP1 to promote S-phase entry and tumorigenesis (PMID:16705184, PMID:19451188), suppresses SEMA3F to enhance tumor invasion (PMID:20388805), and restrains E2A-dependent Tcf7/TCF1, IL-10, and Socs3 induction to control CD8+ T cell, NK cell, and Treg fate (PMID:23536629, PMID:24723679, PMID:26795246, PMID:33857289, PMID:30413714). Beyond E-proteins, ID2 directly binds the unphosphorylated forms of all three Rb-family pocket proteins (pRb, p107, p130) via its HLH domain, neutralizing their growth-suppressive activity and serving as a mediator of Myc oncogenic signaling (PMID:7926730, PMID:8649364, PMID:11034201). ID2 also acts epigenetically, disrupting the Tcf3-Tal1 complex to block recruitment of the histone demethylase LSD1 and preserve permissive chromatin at target promoters (PMID:38287103). ID2 protein levels are tightly controlled by proteasomal degradation through N-terminal ubiquitination, APC/C(Cdh1)-mediated D-box recognition, and phosphorylation-dependent turnover, while DYRK1A/B phosphorylation of Thr27 gates its interaction with the VHL ligase to control HIF2α stability (PMID:14733935, PMID:16810178, PMID:26756672, PMID:26735018). ID2 transcription is directly driven by Myc, β-catenin/TCF, C/EBPβ, BMP4, and FSH/cAMP and repressed by TGF-β effectors, Gfi-1, Ebf1, and Mtg16, integrating diverse upstream signals into developmental and oncogenic programs (PMID:11572874, PMID:12824180, PMID:15809228, PMID:16547003, PMID:14761970, PMID:20453161, PMID:19122139, PMID:24980046). Note that discovery (PMID:32510829) describes the FANCD2-FANCI "ID2" DNA-repair complex, an unrelated entity sharing the abbreviation, not the ID2 HLH protein.

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1991 High

    Established the founding biochemical activity of ID2: how a protein without a DNA-binding domain regulates transcription, by showing it selectively dimerizes with and inhibits a defined class of bHLH factors.

    Evidence cDNA cloning and in vitro protein interaction/DNA-binding inhibition assays with defined bHLH partners

    PMID:1922066

    Open questions at the time
    • Did not establish in vivo targets or physiological lineages affected
    • Selectivity basis for class I vs class II bHLH partners left structurally undefined
  2. 1996 High

    Resolved whether ID2's growth control acts beyond E-proteins by demonstrating direct HLH-mediated binding to all three Rb-family proteins and reversal of Rb/CDK-inhibitor-induced arrest, defining a second mechanistic arm.

    Evidence In vitro binding, reciprocal co-IP in Saos-2 cells, deletion mutagenesis, and cell-cycle assays (builds on the 1994 pRb finding)

    PMID:7926730 PMID:8649364

    Open questions at the time
    • Stoichiometry and competition between Rb-binding and E-protein-binding roles unresolved
    • Did not address physiological contexts where Rb binding dominates
  3. 2000 High

    Placed ID2 in an oncogenic signaling hierarchy by showing Myc drives ID2 to inactivate Rb, with genetic epistasis rescuing developmental defects, establishing ID2 as a Myc effector.

    Evidence Id2-Rb double-knockout mouse epistasis plus N-myc amplified neuroblastoma cell biochemistry

    PMID:11034201

    Open questions at the time
    • Relative contribution of Rb inactivation vs E-protein sequestration to the rescue not separated
  4. 2003 High

    Defined ID2 as a transcriptionally controlled node where upstream signals converge, showing context-dependent induction (TGF-β in DCs) versus repression (TGF-β in epithelia via Mad-Max promoter switching).

    Evidence Id2-knockout mice, cytokine stimulation, promoter ChIP, and gel-shift across cell types; promoter direct activation also shown for β-catenin/TCF and C/EBPβ

    PMID:11572874 PMID:12598895 PMID:12824180 PMID:15809228

    Open questions at the time
    • Mechanistic basis for opposite TGF-β outcomes across lineages not unified
    • Promoter element interplay between competing inputs not mapped
  5. 2006 High

    Mechanistically connected E-protein inhibition to specific cell-cycle and developmental outputs by identifying p57Kip2 as an E47 target blocked by ID2, and demonstrating bHLH-target control in neurons, pancreas, and heart.

    Evidence Inducible E47/Id2 systems with RNAi rescue, BMP4 stimulation with NeuroD co-IP, and Tbx5/Nkx2-5 promoter and genetic studies

    PMID:16547003 PMID:16705184 PMID:17604724

    Open questions at the time
    • Tissue-specific E-protein partner identity not always defined
    • Quantitative threshold of E-protein titration needed for fate switches unknown
  6. 2006 High

    Resolved how ID2 protein abundance is set, identifying N-terminal ubiquitination and APC/C(Cdh1) D-box-dependent degradation, with stabilized ID2 driving axonal growth via suppression of bHLH targets.

    Evidence In vitro and cell ubiquitination assays, N-/C-terminal tagging, D-box mutagenesis, Cdh1 RNAi, and neuronal growth assays

    PMID:14733935 PMID:16810178

    Open questions at the time
    • Identity of the N-terminal ubiquitination E3 ligase not established
    • Interplay between the two degradation routes not quantified
  7. 2013 Medium

    Extended the E-protein-titration model to adaptive and innate immunity, defining ID2 targets (Tcf7, Il10, Socs3) that govern effector-versus-memory CD8+ fate, NK homeostasis, and Treg plasticity.

    Evidence Conditional and germline Id2 knockouts with E2A reporter/ChIP analysis plus genetic rescue (Socs3 deletion, IL-15)

    PMID:23536629 PMID:24723679 PMID:26795246 PMID:30413714 PMID:33857289

    Open questions at the time
    • Each axis characterized in a single lineage; cross-lineage generality of individual targets unconfirmed
    • Direct vs indirect status of some targets relies on reporter assays
  8. 2016 High

    Uncovered a phosphorylation-gated, oxygen-sensitive function: DYRK1A/B phosphorylation of Thr27 controls ID2's binding to the VHL complex, coupling ID2 to HIF2α stabilization, while N-terminal phosphorylation governs proteasomal turnover.

    Evidence In vitro kinase, co-IP, ubiquitylation, phospho-mutant analysis (VHL/HIF2α); MS-mapped sites with half-life and PP2A assays (turnover)

    PMID:26735018 PMID:26756672

    Open questions at the time
    • Whether phospho-regulation of stability and of VHL binding act on the same pool unclear
    • In vivo relevance of HIF2α axis outside glioblastoma not broadly tested
  9. 2024 High

    Established a chromatin-level mechanism beyond simple E-protein sequestration: ID2's HLH domain disrupts the Tcf3-Tal1 complex to block LSD1 recruitment, preserving permissive H3K4me2 and shaping CD8+ T cell exhaustion programs.

    Evidence Id2-knockout mice, co-IP of Id2-HLH with Tcf3-Tal1, ChIP-seq/ATAC-seq, and LSD1 inhibitor rescue

    PMID:38287103

    Open questions at the time
    • Generality of LSD1-blocking mechanism at other ID2-regulated promoters untested
    • Whether this acts in concert with or independently of E-protein heterodimerization unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ID2 partitions its activity among E-protein sequestration, Rb-family binding, VHL/HIF2α control, and chromatin remodeling within a single cell, and what determines which mechanism dominates in a given lineage.
  • No structural model distinguishing Rb-binding from E-protein-binding HLH interfaces in vivo
  • No quantitative framework relating ID2 dose to choice of effector mechanism
  • Integrated regulation by the multiple degradation/phosphorylation routes not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 4 GO:0140313 molecular sequestering activity 3
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
E2A/E47NEUROD1RB1RBL1RBL2TCF3VHLZEB1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 Id2 contains a helix-loop-helix (HLH) motif but lacks the basic DNA-binding domain; it selectively heterodimerizes with and inhibits one class of bHLH transcription factors (typified by E2A/E47 and E2B/m3) but not another class (TFE3, USF, AP4). Id2 also homodimerizes poorly. cDNA cloning, chromosome mapping, in vitro protein interaction and DNA-binding inhibition assays Molecular and cellular biology High 1922066
1994 Id2 physically binds unphosphorylated pRb via its HLH domain (an Id2 mutant lacking the HLH domain fails to bind); the interaction requires the E1A/large T-binding pocket of pRb. Id2 expression reverses pRb-mediated growth arrest without changing pRb phosphorylation state. In vitro binding assay with cell lysates, in vivo cross-linked co-immunoprecipitation in transfected SAOS-2 cells, deletion mutagenesis, cell proliferation/S-phase analysis Genes & development High 7926730
1996 Id2, but not Id1 or Id3, binds in vitro to pRb, p107, and p130 (all three Rb family members), and in vivo association of Id2 with p107 and p130 is detected in transfected Saos-2 cells. Id2 specifically reverses cell cycle arrest induced by each Rb family member and by the CDK inhibitors p16 and p21 (p21 reversal is partial and pRb-dependent). Id2 overexpression decreases cyclin D1 protein/mRNA and disrupts cyclin D1-Cdk4 complexes. In vitro binding assay, transient transfection with co-immunoprecipitation, cell cycle progression assays, Western blot, Northern blot Molecular and cellular biology High 8649364
2000 Id2 overexpression driven by Myc oncoproteins (N-Myc and c-Myc) inactivates Rb family proteins, enabling cell-cycle progression. In Id2-Rb double-knockout embryos, neurogenesis and hematopoiesis defects are rescued compared to each single knockout, establishing Id2 as a mediator of Myc oncogenic signaling through Rb inactivation. Double-knockout mouse genetics (epistasis), N-myc overexpression/amplification in neuroblastoma cell lines, transcriptional activation assays, molar ratio analysis of Id2 vs. active Rb Nature High 11034201
2001 Id2 is a transcriptional target of the β-catenin/TCF pathway in colon carcinoma; a TCF4-binding motif in the Id2 promoter is required for activation (identified by EMSA/supershift and abolished by site-directed mutagenesis). β-catenin up-regulates Id2 protein and increases anchorage-independent survival. Id2 promoter reporter assays, EMSA with supershift, site-directed mutagenesis, β-catenin overexpression/knockdown, anchorage-independent growth assay The Journal of biological chemistry High 11572874
2003 TGF-β signaling induces Id2 expression in dendritic cells, and Id2 represses B cell-specific genes in DCs, revealing a TGF-β→Id2 signaling axis that governs lineage choice between B cell and DC progenitors. Id2-knockout mouse analysis, in vitro TGF-β stimulation of DC cultures, gene expression profiling, in vivo DC subset analysis Nature immunology High 12598895
2003 TGF-β inhibits Id2 expression in human and mouse epithelial cells; this repression occurs via induction of Mad2/Mad4, which replaces Myc-Max complexes with Mad-Max complexes on the Id2 promoter, linking TGF-β cytostatic signaling to Id2 downregulation. Northern/Western blot in multiple epithelial cell lines, promoter ChIP (Myc-Max vs. Mad-Max occupancy), gel-shift assays The Journal of biological chemistry High 12824180
2004 Id2 is degraded by the ubiquitin-proteasome system via ubiquitination at its N-terminal α-amino group (N-terminal ubiquitination). Lysine-less Id2 is still efficiently degraded by the proteasome; N-terminal Myc-tag fusion stabilizes Id2, whereas C-terminal tag does not. Deletion of the first 15 N-terminal residues also stabilizes Id2, implicating this region as the E3 ligase recognition element. In vitro and cell-based ubiquitination assays, proteasome inhibitor experiments, N-terminal vs. C-terminal tagging, deletion mutagenesis, pulse-chase/stability assays Biochemical and biophysical research communications High 14733935
2005 Polycystin-2 (PC2) directly interacts with Id2, and this interaction is regulated by polycystin-1 (PC1)-dependent phosphorylation of PC2. Id2 suppresses p21 induction by PC1 or PC2. Enhanced Id2 nuclear localization is observed in cystic kidneys, and RNAi-mediated Id2 knockdown corrects hyperproliferation of PC1 mutant cells. Co-immunoprecipitation, RNAi knockdown, nuclear fractionation/localization in cystic kidney tissue and cells, functional proliferation assays Nature cell biology High 16311606
2006 APC/C(Cdh1) ubiquitin ligase targets Id2 for proteasomal degradation through a conserved D-box (destruction box) motif. Id2 interacts with APC/C core subunits and Cdh1 in neurons; Cdh1 depletion stabilizes Id proteins; D-box mutants of Id2 fail to bind Cdh1 and remain stable when APC/C(Cdh1) is active. Stabilized Id2 enhances axonal growth and overcomes myelin inhibitory signals by preventing accumulation of the Nogo receptor (a bHLH target gene product). Co-immunoprecipitation in primary neurons, D-box mutagenesis, Cdh1 RNAi/knockdown, in vitro and in vivo axonal growth assays, gene expression analysis Nature High 16810178
2005 C/EBPβ is a direct transcriptional activator of the Id2 gene; the most proximal C/EBPβ-binding site in the Id2 promoter is responsible for transactivation, as confirmed by EMSA and ChIP. Id2 expression is reduced in C/EBPβ-deficient mammary glands. Id2 promoter reporter assays, EMSA, ChIP, Northern blot in C/EBPβ-knockout mammary glands, C/EBPβ-ERT nuclear translocation system Nucleic acids research High 15809228
2006 Id2 promotes S-phase entry in neural cells by preventing E-protein (E47)-mediated activation of the CDK inhibitor p57Kip2. E47 directly activates p57Kip2 expression, and Id2 blocks this activation; p57Kip2 silencing by RNAi fully reverses E47-mediated cell cycle arrest. Gene expression profiling, RNAi knockdown, cell cycle analysis, in neuroblastoma cell lines engineered with inducible E47 and Id2 Molecular and cellular biology High 16705184
2007 Id2 functions downstream of Tbx5 and Nkx2-5 in a molecular pathway required for cardiac ventricular conduction system specification. Compound haploinsufficiency of Tbx5/Id2 prevents embryonic conduction system specification; a 1.2 kb Id2 promoter fragment is cooperatively regulated by Nkx2-5 and Tbx5 in vitro and is sufficient for conduction-system-specific expression in vivo. Id2-knockout and compound haploinsufficient mouse genetics, SAGE transcriptional profiling of microdissected conduction system, promoter reporter assays, in vivo transgenic reporter Cell High 17604724
2008 Id2 regulates erythroid development via direct interaction with transcription factor PU.1, modulating PU.1 and GATA-1 activities. Id2 also intrinsically inhibits B cell development through antagonism of E2A (E47). Id2 knockout mouse analysis, retroviral overexpression in hematopoietic progenitors, shRNA knockdown, co-immunoprecipitation/interaction studies with PU.1 Blood Medium 18523151
2009 Ebf1 transcriptionally represses Id2 (and Id3) during B-lineage specification; enforced Ebf1 in IL-7Rα−/− bone marrow dramatically reduces Id2/Id3 mRNA and restores B cell differentiation. Overexpression of Id2 alone blocks B cell specification at the prepro-B stage by inhibiting E2A activity. Retroviral overexpression and knockout mouse genetics, qRT-PCR, in vivo B cell reconstitution assays Proceedings of the National Academy of Sciences of the United States of America Medium 19122139
2006 BMP4 induces Id2 expression in pancreatic epithelial progenitors, and BMP4-stimulated Id2 binds to the bHLH transcription factor NeuroD, blocking NeuroD-dependent differentiation and instead promoting progenitor expansion. BMP4 stimulation of AR42J cells, co-immunoprecipitation of Id2 with NeuroD, BMP4 neutralization in a mouse islet regeneration model, proliferation assays The Journal of biological chemistry Medium 16547003
2009 Id2-mediated sequestration of E12/E47 bHLH factors suppresses p27KIP1 promoter activity, reducing p27KIP1 expression. Re-expression of p27KIP1 in Id2-overexpressing Id2−/− fibroblasts reverts hyperproliferation and tumorigenicity, identifying the Id2/E12/E47/p27KIP1 axis as a mechanism of Id2-driven oncogenesis. Id2 deletion mutagenesis, re-expression in Id2−/− fibroblasts, promoter reporter assays, flow cytometry, subcutaneous tumor grafting in athymic mice Carcinogenesis Medium 19451188
2010 Id2 represses SEMA3F expression through the E47/Id2 pathway; Id2 blocks E47-mediated direct activation of two E-box sites in the SEMA3F promoter. C-Myc drives Id2 overexpression, which in turn suppresses SEMA3F and promotes tumor cell migration and invasion. SEMA3F promoter reporter assay with E-box mutagenesis, E47 overexpression/Id2 overexpression in low vs. high metastatic cell lines, migration/invasion assays, silencing of SEMA3F Cancer research Medium 20388805
2010 Gfi-1 directly binds to three conserved regions in the Id2 promoter and represses Id2 promoter activity. Id2 knockdown or haploinsufficiency partially rescues B cell and myeloid development defects in Gfi-1−/− mice, placing Id2 downstream of Gfi-1 in hematopoietic transcriptional networks. ChIP, promoter reporter assay, Id2/Gfi-1 double knockout/heterozygous mouse genetics, in vivo B cell and myeloid reconstitution Blood Medium 20453161
2013 Id2 inhibits E2A (E47)-mediated direct transcriptional activation of Tcf7 (encoding TCF1), restraining memory CD8+ T cell differentiation. Loss of Id2 leads to E2A-dependent increase of Tcf7 and Eomesodermin expression, redirecting effector CD8+ T cells toward a memory fate. Id2-knockout mouse, retroviral E2A overexpression, gene expression profiling, chromatin/luciferase reporter assays Journal of immunology Medium 23536629
2013 Id2 represses E2A-mediated transactivation of the IL-10 locus (Il10) in T cells; Id2-deficient T cells overexpress IL-10 in vitro and in vivo during infection, demonstrating that the Id2/E2A axis limits IL-10 production during effector T cell responses. Id2-knockout mouse, IL-10 reporter/ChIP analysis, graft-versus-host disease model, influenza infection model Blood Medium 24723679
2014 Mtg16 directly represses Id2 transcription in dendritic cell progenitors (identified by genome-wide DNA-binding analysis); loss of Mtg16 leads to aberrant Id2 induction in pDC progenitors, and Id2 deletion rescues impaired pDC development in Mtg16-deficient mice. Mtg16-knockout mouse, genome-wide ChIP-seq of Mtg16, Id2/Mtg16 double-knockout genetics, flow cytometric DC subset analysis The Journal of experimental medicine High 24980046
2016 DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Phosphorylated ID2 cannot bind the VHL ubiquitin ligase complex; unphosphorylated ID2 binds VHL, displaces Cullin 2, and impairs HIF2α ubiquitylation and degradation. Hypoxia inactivates DYRK1A/1B (via PHD1 oxygen sensor) to reduce Thr27 phosphorylation and allow ID2–VHL interaction and HIF2α stabilization. In vitro kinase assay (DYRK1A/B phosphorylation of ID2), co-immunoprecipitation of ID2 with VHL complex, ubiquitylation assays, phospho-mutant ID2 expression, tumor growth assays in glioblastoma Nature High 26735018
2016 ID2 regulates NK cell homeostasis by repressing multiple E-protein target genes including Socs3; ID2 deletion in mature NK cells impairs IL-15 receptor signaling and metabolic function, and these defects are rescued by strong IL-15 stimulation or genetic Socs3 ablation. Conditional Id2 knockout in NK cells, IL-15 stimulation rescue experiments, Socs3 genetic deletion rescue, gene expression analysis Immunity High 26795246
2016 Phosphorylation of Id2 near its N-terminus promotes its proteasomal degradation; Id2 mutants lacking these phosphorylation sites have longer half-lives and reduced proteasome-mediated degradation, and neural precursor cells expressing de-phosphorylated Id2 proliferate more rapidly. PP2A phosphatase expression stabilizes Id2 levels. Mass spectrometry identification of phosphorylation sites, stable expression of phospho-mutant Id2 in Id2−/− neural precursor cells, pulse-chase/half-life assays, proteasome inhibition, PP2A manipulation Stem cells High 26756672
2017 Id2 specifies embryonic Lgr5+ intestinal stem cell progenitors by restricting Wnt signaling activity; in the absence of Id2, Wnt target genes are prematurely activated and intestinal epithelial cells differentiate into Lgr5+ cells as early as E9.5. Id2-deficient embryonic epithelial cells strongly activate Wnt targets ex vivo. Id2-knockout mice, cell fate mapping, Wnt target gene expression analysis, ex vivo intestinal epithelial organoid cultures The EMBO journal Medium 28077488
2018 Pro-inflammatory cytokines enhance Id2 expression in Treg cells; Id2 sequesters E2A transcription activator, reducing Foxp3 expression and inducing TH17-related cytokines, thereby driving Treg-to-TH17 plasticity. Treg-specific ectopic Id2 expression in mice reduces the Treg compartment and exacerbates autoimmunity. In vitro iTreg differentiation with Id2 overexpression, Id2 Treg-specific transgenic mice, cellular fate-mapping, EAE model Nature communications Medium 30413714
2020 Monoubiquitination of FANCD2 (within the FANCD2/FANCI = ID2 complex) promotes a large-scale conformational change that increases the complex's affinity for double-stranded DNA, causing it to encircle dsDNA. Monoubiquitination of FANCI protects the ubiquitin on FANCD2 from USP1-UAF1 deubiquitination, with key hydrophobic residues of FANCI's ubiquitin being critical for this protection. Cryo-EM structural analysis, in vitro ubiquitination assays, DNA-binding affinity measurements, deubiquitination protection assays with USP1-UAF1 EMBO reports High 32510829
2021 Id2 supports NK cell effector maturation by setting a threshold for TCF1 (encoded by Tcf7); ID2-deficient NK cells show increased TCF1 expression that arrests their maturation, reduces surface receptor expression, impairs IFN-γ production, and reduces ability to clear metastatic melanoma. Conditional Id2-knockout mouse, gene expression profiling, flow cytometry of NK cell maturation markers, cytokine stimulation assays, in vivo melanoma clearance assay The Journal of experimental medicine Medium 33857289
2021 TGF-β signaling decelerates airway basal cell proliferation during development by inhibiting Id2 expression; in adult tissue regeneration, reduced TGF-β signaling restores Id2 expression to initiate regeneration. Persistent Id2 expression drives basal cell hyperplasia resembling a pre-cancerous state. Temporal single-cell transcriptomics, Id2 overexpression and Tgfbr2 conditional knockout in airway epithelium, genetic validation experiments Developmental cell Medium 34129836
2024 Id2, via its HLH domain, binds and disrupts assembly of the Tcf3-Tal1 transcriptional regulatory complex, preventing Tcf3 from recruiting the histone demethylase LSD1 to the Slamf6 promoter. This preserves the permissive H3K4me2 mark on Tcf3-occupied E-boxes in the Slamf6 promoter, increasing chromatin accessibility and promoting generation of Slamf6+ progenitor exhausted CD8+ T cells. Id2-knockout mouse, ChIP-seq for H3K4me2 and chromatin accessibility (ATAC-seq), co-immunoprecipitation of Id2-HLH with Tcf3-Tal1 complex, LSD1 inhibitor rescue experiments Cellular & molecular immunology High 38287103
2002 Id2 inhibits BETA2/NeuroD binding to its E-box target sequence; coexpression of Id2 blocks BETA2/NeuroD-mediated E-box-driven transcription in a dose-dependent manner in neuroendocrine HIT cells. Yeast two-hybrid, EMSA, co-expression reporter assays in HIT and HeLa cells Experimental & molecular medicine Medium 12526101
2007 All-trans retinoic acid (atRA) suppresses Id2 expression in HaCaT keratinocytes by recruiting LSD1 histone demethylase to the Wnt-response element (TCF/LEF-binding site) in the Id2 promoter, reducing histone H3/H4 acetylation and H3K4 methylation specifically at this site. siRNA silencing of Id2 phenocopies atRA's antiproliferative effect. ChIP for histone modifications and LSD1 at Id2 promoter WRE, comparison with c-Myc and cyclin D1 WREs, siRNA, cell proliferation assays Oncogene Medium 17310985
2004 FSH and cAMP (via protein kinase A) induce Id2 gene transcription in Sertoli cells; induction requires sequences between −122 and −82 of the Id2 promoter containing ATF/CRE-like and GATA motifs that bind 40–45 kDa proteins. FSH-induced Id2 expression correlates with decreased E-box-binding protein activity and E-box-mediated transcription. Northern blot, Id2 promoter reporter assays, EMSA, FSH and forskolin stimulation, protein kinase A overexpression The Journal of biological chemistry Medium 14761970
2023 METTL3-mediated m6A modification stabilizes ID2 mRNA in pancreatic cancer cells; METTL3 knockdown reduces m6A modification and decreases ID2 mRNA stability. The m6A reader YTHDF2 is required for METTL3-mediated ID2 mRNA stabilization. m6A-seq/MeRIP, METTL3 knockdown, mRNA stability assay, YTHDF2 knockdown, Western blot/qRT-PCR Cancer letters Medium 37196908
2023 BMPR1A activation induces physical interaction between ID2 and ZEB1, sequestering ZEB1 and attenuating transcription of Tgfbr2; this lowers TGFβ responsiveness and prevents excessive EndoMT. In Bmpr1a endothelial-conditional knockout mice, ZEB1-driven Tgfbr2 upregulation causes PAH-like disease. Co-immunoprecipitation of ID2 and ZEB1, conditional Bmpr1a endothelial knockout mouse, lineage tracing, siRNA-lipid nanoparticle therapeutic rescue, reporter assays Cardiovascular research Medium 36166408

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Molecular and cellular biology 567 1922066
2000 Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 421 11034201
2003 Transcriptional profiling identifies Id2 function in dendritic cell development. Nature immunology 404 12598895
1994 The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes & development 331 7926730
2000 Id2 and Id3 inhibit development of CD34(+) stem cells into predendritic cell (pre-DC)2 but not into pre-DC1. Evidence for a lymphoid origin of pre-DC2. The Journal of experimental medicine 228 11120774
2006 Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 227 16810178
2007 A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell 223 17604724
1996 Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Molecular and cellular biology 215 8649364
2006 Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nature immunology 206 17086188
2012 Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. The Journal of experimental medicine 200 22430492
2005 Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nature cell biology 164 16311606
1996 Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 164 8922523
2019 An Id2RFP-Reporter Mouse Redefines Innate Lymphoid Cell Precursor Potentials. Immunity 128 30926235
2013 Upregulated H19 contributes to bladder cancer cell proliferation by regulating ID2 expression. The FEBS journal 128 23399020
2001 Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. The Journal of biological chemistry 124 11572874
2014 Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nature immunology 118 24973820
2011 Id2 expression delineates differential checkpoints in the genetic program of CD8α+ and CD103+ dendritic cell lineages. The EMBO journal 117 21587207
2002 Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma. Cancer research 117 11782392
2016 An ID2-dependent mechanism for VHL inactivation in cancer. Nature 105 26735018
2016 The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15. Immunity 104 26795246
2016 Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation. Nature immunology 99 27213691
2004 Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression. Clinical cancer research : an official journal of the American Association for Cancer Research 99 15041724
1993 Neuronal expression of regulatory helix-loop-helix factor Id2 gene in mouse. Developmental biology 99 8224536
2019 An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development. Nature immunology 97 31406377
2018 Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16. Nature immunology 97 30374131
2006 BMP4 regulates pancreatic progenitor cell expansion through Id2. The Journal of biological chemistry 92 16547003
1998 The helix-loop-helix protein Id2 is overexpressed in human pancreatic cancer. Cancer research 87 9731481
2013 Id2-mediated inhibition of E2A represses memory CD8+ T cell differentiation. Journal of immunology (Baltimore, Md. : 1950) 80 23536629
2014 Regulation of ACVR1 and ID2 by cell-secreted exosomes during follicle maturation in the mare. Reproductive biology and endocrinology : RB&E 79 24884710
2003 Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression. The Journal of biological chemistry 76 12824180
1996 Id2 expression increases with differentiation of human myeloid cells. Blood 76 8652837
2010 Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer research 72 20388805
2006 E Proteins and Id2 converge on p57Kip2 to regulate cell cycle in neural cells. Molecular and cellular biology 70 16705184
2009 Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage. Proceedings of the National Academy of Sciences of the United States of America 69 19122139
2005 Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. American journal of physiology. Cell physiology 66 16120655
1995 Coordinate expression and developmental role of Id2 protein and TAL1/E2A heterodimer in erythroid progenitor differentiation. Blood 64 7540882
2021 Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex. Nature neuroscience 62 33619404
2018 Inflammation-induced Id2 promotes plasticity in regulatory T cells. Nature communications 62 30413714
2003 TH2 dominance and defective development of a CD8+ dendritic cell subset in Id2-deficient mice. The Journal of allergy and clinical immunology 61 12532109
2019 LncRNA ID2-AS1 suppresses tumor metastasis by activating the HDAC8/ID2 pathway in hepatocellular carcinoma. Cancer letters 60 31730902
2023 METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner. Cancer letters 58 37196908
2008 Id2 intrinsically regulates lymphoid and erythroid development via interaction with different target proteins. Blood 58 18523151
2004 Degradation of the Id2 developmental regulator: targeting via N-terminal ubiquitination. Biochemical and biophysical research communications 58 14733935
2019 Blocking lncRNA H19-miR-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury. Aging 57 31170091
2002 Id2 expression during apoptosis and satellite cell activation in unloaded and loaded quail skeletal muscles. American journal of physiology. Regulatory, integrative and comparative physiology 54 12388448
2010 Repression of Id2 expression by Gfi-1 is required for B-cell and myeloid development. Blood 53 20453161
2004 Id2 drives differentiation and suppresses tumor formation in the intestinal epithelium. Cancer research 53 15492237
2005 Differential involvement of PU.1 and Id2 downstream of TGF-beta1 during Langerhans-cell commitment. Blood 51 16223775
2004 Id2 and p53 participate in apoptosis during unloading-induced muscle atrophy. American journal of physiology. Cell physiology 51 15601750
2017 LncRNA H19 regulates ID2 expression through competitive binding to hsa-miR-19a/b in acute myelocytic leukemia. Molecular medicine reports 50 28765931
2012 ID2: A negative transcription factor regulating oligodendroglia differentiation. Journal of neuroscience research 47 22253220
2017 Id2 controls specification of Lgr5+ intestinal stem cell progenitors during gut development. The EMBO journal 46 28077488
2014 ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2. The Journal of experimental medicine 46 24980046
2013 Id2 influences differentiation of killer cell lectin-like receptor G1(hi) short-lived CD8+ effector T cells. Journal of immunology (Baltimore, Md. : 1950) 41 23325888
2011 The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells. Bone 39 21504804
2010 Cellular stress causes reversible, PRKAA1/2-, and proteasome-dependent ID2 protein loss in trophoblast stem cells. Reproduction (Cambridge, England) 39 20876741
2020 Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA. EMBO reports 37 32510829
2005 ID1 and ID2 are retinoic acid responsive genes and induce a G0/G1 accumulation in acute promyelocytic leukemia cells. Leukemia 37 15744343
2021 Airway basal stem cells reutilize the embryonic proliferation regulator, Tgfβ-Id2 axis, for tissue regeneration. Developmental cell 36 34129836
2021 DNA methylation regulates the expression of the negative transcriptional regulators ID2 and ID4 during OPC differentiation. Cellular and molecular life sciences : CMLS 36 34482420
2010 Polycomb repressor complex 2 regulates HOXA9 and HOXA10, activating ID2 in NK/T-cell lines. Molecular cancer 35 20565746
2019 ID2 and GJB2 promote early-stage breast cancer progression by regulating cancer stemness. Breast cancer research and treatment 32 30725231
2004 Id2 haploinsufficiency in mice leads to congenital hydronephrosis resembling that in humans. Genes to cells : devoted to molecular & cellular mechanisms 32 15569159
2013 Batf3 and Id2 have a synergistic effect on Irf8-directed classical CD8α+ dendritic cell development. Journal of immunology (Baltimore, Md. : 1950) 31 24227775
2005 Regulation of Id2 expression by CCAAT/enhancer binding protein beta. Nucleic acids research 31 15809228
2016 Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia. Cancer cell 30 27374225
2024 Id2 epigenetically controls CD8+ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex. Cellular & molecular immunology 29 38287103
2021 The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude. The Journal of experimental medicine 29 33857289
2007 Apoptosis and Id2 expression in diaphragm and soleus muscle from the emphysematous hamster. American journal of physiology. Regulatory, integrative and comparative physiology 29 17395785
2002 Inhibition of BETA2/NeuroD by Id2. Experimental & molecular medicine 29 12526101
2022 ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation. Scientific reports 28 35149717
2015 TNFα signaling regulates cystic epithelial cell proliferation through Akt/mTOR and ERK/MAPK/Cdk2 mediated Id2 signaling. PloS one 28 26110849
2014 The Fanconi anemia ID2 complex: dueling saxes at the crossroads. Cell cycle (Georgetown, Tex.) 28 25486561
2013 Id3 and Id2 act as a dual safety mechanism in regulating the development and population size of innate-like γδ T cells. Journal of immunology (Baltimore, Md. : 1950) 28 24379125
2023 Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis. Journal of neuroinflammation 27 37344856
2022 The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer. Experimental & molecular medicine 27 35729325
2019 The Transcriptional Regulator Id2 Is Critical for Adipose-Resident Regulatory T Cell Differentiation, Survival, and Function. Journal of immunology (Baltimore, Md. : 1950) 27 31201238
2014 Id2 mediates oligodendrocyte precursor cell maturation arrest and is tumorigenic in a PDGF-rich microenvironment. Cancer research 27 24425046
2013 Id2, Id3 and Id4 overcome a Smad7-mediated block in tumorigenesis, generating TGF-β-independent melanoma. Carcinogenesis 27 24343358
2017 ID2 promotes survival of glioblastoma cells during metabolic stress by regulating mitochondrial function. Cell death & disease 26 28206987
2014 Id2 represses E2A-mediated activation of IL-10 expression in T cells. Blood 26 24723679
2009 The intracellular localization of ID2 expression has a predictive value in non small cell lung cancer. PloS one 26 19129913
2023 Quercetin prevents the ferroptosis of OPCs by inhibiting the Id2/transferrin pathway. Chemico-biological interactions 25 37230155
2021 ID2 Inhibits Bladder Cancer Progression and Metastasis via PI3K/AKT Signaling Pathway. Frontiers in cell and developmental biology 25 34746132
2019 Peroxiredoxin 4 suppresses anoikis and augments growth and metastasis of hepatocellular carcinoma cells through the β-catenin/ID2 pathway. Cellular oncology (Dordrecht, Netherlands) 25 31256347
2007 Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes. Oncogene 25 17310985
1995 Expression of Id2 and Id3 mRNA in human lymphocytes. Leukemia research 25 8632670
2003 ID2 expression is not associated with MYCN amplification or expression in human neuroblastomas. Cancer research 24 12670915
2004 The Id2 transcriptional repressor is induced by follicle-stimulating hormone and cAMP. The Journal of biological chemistry 23 14761970
2023 BMPR1A promotes ID2-ZEB1 interaction to suppress excessive endothelial to mesenchymal transition. Cardiovascular research 22 36166408
2016 Id2 Mediates Differentiation of Labyrinthine Placental Progenitor Cell Line, SM10. Stem cells and development 22 27168216
2018 ID2 protects retinal pigment epithelium cells from oxidative damage through p-ERK1/2/ID2/NRF2. Archives of biochemistry and biophysics 21 29753724
2016 Phosphorylation Regulates Id2 Degradation and Mediates the Proliferation of Neural Precursor Cells. Stem cells (Dayton, Ohio) 21 26756672
2016 BMP4 promotes mouse iPS cell differentiation to male germ cells via Smad1/5, Gata4, Id1 and Id2. Reproduction (Cambridge, England) 21 27864336
2021 TOB1 Blocks Intestinal Mucosal Inflammation Through Inducing ID2-Mediated Suppression of Th1/Th17 Cell Immune Responses in IBD. Cellular and molecular gastroenterology and hepatology 20 34920145
2022 GDF-11 promotes human trophoblast cell invasion by increasing ID2-mediated MMP2 expression. Cell communication and signaling : CCS 19 35705978
2013 Elevated Id2 expression results in precocious neural stem cell depletion and abnormal brain development. Stem cells (Dayton, Ohio) 19 23390122
2009 Sequestration of E12/E47 and suppression of p27KIP1 play a role in Id2-induced proliferation and tumorigenesis. Carcinogenesis 19 19451188
2005 Zebrafish id2 developmental expression pattern contains evolutionary conserved and species-specific characteristics. Developmental dynamics : an official publication of the American Association of Anatomists 19 16252281
2004 Id2 is dispensable for Myc-induced epidermal neoplasia. Molecular and cellular biology 19 14966287

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