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ID2 (Inhibitor Of DNA Binding 2, Dominant Negative Helix-Loop-Helix Protein)

Written2014-06Menno C van Zelm
Dept Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

(Note : for Links provided by Atlas : click)


Other aliasGIG8
LocusID (NCBI) 3398
Atlas_Id 436
Location 2p25.1  [Link to chromosome band 2p25]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Description The gene spans 5608 bp containing 5 exons of which 2 (exons 3 and 4) are protein-encoding.
Transcription The ID2 gene has 4 transcripts, of which 3 can generate functional protein: ID2-001 (2041bp) contains all 5 exons, ID2-201 (1362 bp) contains 3 exons and ID2-002 contains 2 exons. ID2-003 (474 bp) contains a retained intron.
Pseudogene A pseudogene of ID2 is located on chromosome 3.


Description ID2 belongs to the helix-loop-helix (HLH) protein family. It is composed by 134 aa and belongs to a subgroup HLH family members (ID1, ID2, ID3, ID4) that lack a basic DNA-binding domain. ID proteins form heterodimers with class I basic HLH-group members such as MyoD (Langlands et al., 1997), NEDD9 (Law et al., 1999), and E2A gene products E12 and E47. ID2 has a main domain located on 38-79 aa responsible for the helix-loop-helix conformation. In addition, Id2 contains a 10 aa motif that is responsible for the nuclear export signaling.
Expression Expression of ID2 is found in the brain, ovary, liver, lung, thyroid gland and prostate and several subsets of leukocytes. ID2 expression is especially high in Natural Killer (NK-) cells, but is also found in CD4+ T cells, CD8+ T cells, monocytes and precursor B cells.
Localisation Nucleus.
Function Although it does not bind directly to DNA, by binding basic helix-loop-helix transcription factors through its HLH motif, ID2 may control tissue-specific genes related to cell growth, proliferation and differentiation (Hara et al., 1994; Iavarone et al., 1994). ID2 functions in cell fate decisions in early leukocyte development. Specifically, ID2 is required for NK-cell, innate lymphoid and lymphoid tissue inducer cells (Boos et al., 2007; Moro et al., 2010; Yokota et al., 1999). Furthermore, ID2 functions in the development of several dendritic cell subsets: Langerhans cells, cutaneous dendritic cells and splenic CD8a+ dendritic cells (Hacker et al., 2003). Although ID2 seems redundant for T-cell development in thymus, ID2 promotes NKT-cell development (Verykokakis et al., 2013), and it is involved in effector differentiation (Masson et al., 2013), as well as γδT cell homeostasis (Zhang et al., 2014). Finally, ID2 inhibits progression of precursor-B-cell development (Hara et al., 1997; Jensen et al., 2013), as well as activation-induced deaminase expression during B-cell responses (Gonda et al., 2003), likely through inhibition of E47 (Sayegh et al., 2003).
Besides leukocytes, ID2 has been found to function in erythrocyte development (Ji et al., 2008), enterocyte precursor and lung epithelial cell differentiation in mice (Rawlins et al., 2009). Furthermore, female mice lacking ID2 show lactation defects (Mori et al., 2000), and male mice have impaired spermatogenesis (Sablitzky et al., 1998).
Homology ID2 is highly conserved in vertebrates, including mammals, reptiles, and fish.


Germinal No germinal mutations have been reported.
Somatic No somatic mutations have been reported.

Implicated in

Entity Neuroblastoma
Note ID2 functions as a key regulator in the phenotypic transition of neuroblastoma tumor cells (Chakrabarti et al., 2013). Anchorage-dependent (AD) neuroblastoma cells express much higher levels of ID2 than anchorage-independent (AI) cells. Moreover, knockdown of ID2 in AD cells induces an AI phenotype, whereas the opposite is seen upon forced expression of ID2 in AI cells. The function of ID2 in this process is at least in part via negative regulation of the TGFβ/Smad pathway.
Entity Colon carcinoma
Note ID2 expression is upregulated by enhanced beta-catenin signaling and subsequent beta-catenin /TCF mediated transcription. The induction of ID2 expression increases anchorage-independent survival of these cells (Rockman et al., 2001).
Entity Melanoma
Note The transition of melanoma to a more aggressive malignancy is associated with the resistance to growth inhibition by TGF-β (Javelaud et al., 2008). In susceptible cells, TGF-β suppresses ID2 expression and allows p15lnk4b to induce a cell cycle arrest (Schlegel et al., 2009). Upon obtaining resistance to TGF-β, the tumor cells overexpress ID2 and remain in cycle.
Entity Retinoblastoma
Note ID2 is overexpressed due to transcriptional activation by oncoproteins of the Myc family in retinoblastoma, where it is thought to inhibit Retinoblastoma protein family members (Lasorella et al., 2000; Lasorella et al., 2005).
Entity Hodgkin's lymphoma
Note The majority of Hodgkin's lymphomas are derived from germinal center B cells. Still, Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin's lymphoma have a very atypical phenotype. This is the result of overexpression of and Id2, which inhibit the function of the B cell-determining transcription factor E2A (Mathas et al., 2006; Renne et al., 2006). The mechanism resulting in ID2 overexpression, nor the impact of ID2 on cell cycle progression in HRS cells have been demonstrated experimentally yet (Cotta and Medeiros, 2008).


Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity.
Boos MD, Yokota Y, Eberl G, Kee BL.
J Exp Med. 2007 May 14;204(5):1119-30. Epub 2007 Apr 23.
PMID 17452521
A mechanism linking Id2-TGFβ crosstalk to reversible adaptive plasticity in neuroblastoma.
Chakrabarti L, Wang BD, Lee NH, Sandler AD.
PLoS One. 2013 Dec 23;8(12):e83521. doi: 10.1371/journal.pone.0083521. eCollection 2013.
PMID 24376712
Expression of helix-loop-helix proteins in classical hodgkin lymphoma: a possible explanation for a characteristic immunophenotype.
Cotta CV, Medeiros LJ.
Adv Anat Pathol. 2008 Mar;15(2):97-104. doi: 10.1097/PAP.0b013e3181661363.
PMID 18418090
The balance between Pax5 and Id2 activities is the key to AID gene expression.
Gonda H, Sugai M, Nambu Y, Katakai T, Agata Y, Mori KJ, Yokota Y, Shimizu A.
J Exp Med. 2003 Nov 3;198(9):1427-37. Epub 2003 Oct 27.
PMID 14581609
Transcriptional profiling identifies Id2 function in dendritic cell development.
Hacker C, Kirsch RD, Ju XS, Hieronymus T, Gust TC, Kuhl C, Jorgas T, Kurz SM, Rose-John S, Yokota Y, Zenke M.
Nat Immunol. 2003 Apr;4(4):380-6. Epub 2003 Feb 24.
PMID 12598895
Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors.
Hara E, Hall M, Peters G.
EMBO J. 1997 Jan 15;16(2):332-42.
PMID 9029153
Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts.
Hara E, Yamaguchi T, Nojima H, Ide T, Campisi J, Okayama H, Oda K.
J Biol Chem. 1994 Jan 21;269(3):2139-45.
PMID 8294468
The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein.
Iavarone A, Garg P, Lasorella A, Hsu J, Israel MA.
Genes Dev. 1994 Jun 1;8(11):1270-84.
PMID 7926730
Transforming growth factor-beta in cutaneous melanoma.
Javelaud D, Alexaki VI, Mauviel A.
Pigment Cell Melanoma Res. 2008 Apr;21(2):123-32. doi: 10.1111/j.1755-148X.2008.00450.x. (REVIEW)
PMID 18426405
Increased ID2 levels in adult precursor B cells as compared with children is associated with impaired Ig locus contraction and decreased bone marrow output.
Jensen K, Rother MB, Brusletto BS, Olstad OK, Dalsbotten Aass HC, van Zelm MC, Kierulf P, Gautvik KM.
J Immunol. 2013 Aug 1;191(3):1210-9. doi: 10.4049/jimmunol.1203462. Epub 2013 Jul 3.
PMID 23825313
Id2 intrinsically regulates lymphoid and erythroid development via interaction with different target proteins.
Ji M, Li H, Suh HC, Klarmann KD, Yokota Y, Keller JR.
Blood. 2008 Aug 15;112(4):1068-77. doi: 10.1182/blood-2008-01-133504. Epub 2008 Jun 3.
PMID 18523151
Differential interactions of Id proteins with basic-helix-loop-helix transcription factors.
Langlands K, Yin X, Anand G, Prochownik EV.
J Biol Chem. 1997 Aug 8;272(32):19785-93.
PMID 9242638
Id2 mediates tumor initiation, proliferation, and angiogenesis in Rb mutant mice.
Lasorella A, Rothschild G, Yokota Y, Russell RG, Iavarone A.
Mol Cell Biol. 2005 May;25(9):3563-74.
PMID 15831462
Dimerization of the docking/adaptor protein HEF1 via a carboxy-terminal helix-loop-helix domain.
Law SF, Zhang YZ, Fashena SJ, Toby G, Estojak J, Golemis EA.
Exp Cell Res. 1999 Oct 10;252(1):224-35.
PMID 10502414
Id2-mediated inhibition of E2A represses memory CD8+ T cell differentiation.
Masson F, Minnich M, Olshansky M, Bilic I, Mount AM, Kallies A, Speed TP, Busslinger M, Nutt SL, Belz GT.
J Immunol. 2013 May 1;190(9):4585-94. doi: 10.4049/jimmunol.1300099. Epub 2013 Mar 27.
PMID 23536629
Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma.
Mathas S, Janz M, Hummel F, Hummel M, Wollert-Wulf B, Lusatis S, Anagnostopoulos I, Lietz A, Sigvardsson M, Jundt F, Johrens K, Bommert K, Stein H, Dorken B.
Nat Immunol. 2006 Feb;7(2):207-15. Epub 2005 Dec 20.
PMID 16369535
Lactation defect in mice lacking the helix-loop-helix inhibitor Id2.
Mori S, Nishikawa SI, Yokota Y.
EMBO J. 2000 Nov 1;19(21):5772-81.
PMID 11060028
Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.
Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, Furusawa J, Ohtani M, Fujii H, Koyasu S.
Nature. 2010 Jan 28;463(7280):540-4. doi: 10.1038/nature08636. Epub 2009 Dec 20.
PMID 20023630
The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells.
Rawlins EL, Clark CP, Xue Y, Hogan BL.
Development. 2009 Nov;136(22):3741-5. doi: 10.1242/dev.037317.
PMID 19855016
Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin's lymphoma.
Renne C, Martin-Subero JI, Eickernjager M, Hansmann ML, Kuppers R, Siebert R, Brauninger A.
Am J Pathol. 2006 Aug;169(2):655-64.
PMID 16877363
Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma.
Rockman SP, Currie SA, Ciavarella M, Vincan E, Dow C, Thomas RJ, Phillips WA.
J Biol Chem. 2001 Nov 30;276(48):45113-9. Epub 2001 Sep 25.
PMID 11572874
Stage- and subcellular-specific expression of Id proteins in male germ and Sertoli cells implicates distinctive regulatory roles for Id proteins during meiosis, spermatogenesis, and Sertoli cell function.
Sablitzky F, Moore A, Bromley M, Deed RW, Newton JS, Norton JD.
Cell Growth Differ. 1998 Dec;9(12):1015-24.
PMID 9869302
E-proteins directly regulate expression of activation-induced deaminase in mature B cells.
Sayegh CE, Quong MW, Agata Y, Murre C.
Nat Immunol. 2003 Jun;4(6):586-93. Epub 2003 Apr 28.
PMID 12717431
Id2 suppression of p15 counters TGF-beta-mediated growth inhibition of melanoma cells.
Schlegel NC, Eichhoff OM, Hemmi S, Werner S, Dummer R, Hoek KS.
Pigment Cell Melanoma Res. 2009 Aug;22(4):445-53. doi: 10.1111/j.1755-148X.2009.00571.x. Epub 2009 Apr 24.
PMID 19368689
Essential functions for ID proteins at multiple checkpoints in invariant NKT cell development.
Verykokakis M, Krishnamoorthy V, Iavarone A, Lasorella A, Sigvardsson M, Kee BL.
J Immunol. 2013 Dec 15;191(12):5973-83. doi: 10.4049/jimmunol.1301521. Epub 2013 Nov 15.
PMID 24244015
Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2.
Yokota Y, Mansouri A, Mori S, Sugawara S, Adachi S, Nishikawa S, Gruss P.
Nature. 1999 Feb 25;397(6721):702-6.
PMID 10067894
Id3 and Id2 act as a dual safety mechanism in regulating the development and population size of innate-like γδ T cells.
Zhang B, Lin YY, Dai M, Zhuang Y.
J Immunol. 2014 Feb 1;192(3):1055-63. doi: 10.4049/jimmunol.1302694. Epub 2013 Dec 30.
PMID 24379125


This paper should be referenced as such :
Zelm MC van
ID2 (Inhibitor Of DNA Binding 2, Dominant Negative Helix-Loop-Helix Protein)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(3):168-171.
Free journal version : [ pdf ]   [ DOI ]
On line version :

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)3398
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
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