Alternative titles; symbols
HGNC Approved Gene Symbol: ID2
Cytogenetic location: 2p25.1 Genomic coordinates (GRCh38): 2:8,682,056-8,684,461 (from NCBI)
See inhibitor of DNA binding-1 (ID1; 600349). ID proteins inhibit the functions of basic helix-loop-helix (bHLH) transcription factors in a dominant-negative manner by suppressing their heterodimerization partners through the HLH domains. Members of the ID family also promote cell proliferation, implying a role in the control of cell differentiation.
Hara et al. (1994) cloned and characterized the human ID2 gene.
By study of somatic cell hybrids and by fluorescence in situ hybridization, Mathew et al. (1995) mapped the ID2 gene to chromosome 2p25.
ID2 is able to disrupt the antiproliferative effects of tumor suppressor proteins of the RB family (the 'pocket' proteins: RB1, 614041; p107, 116957; and p130, 180203), thus allowing cell cycle progression (Iavarone et al., 1994; Lasorella et al., 1996). This function correlates with the ability of ID2 to associate physically with active, hypophosphorylated forms of the pocket proteins in vitro and in vivo. By inactivating RB, ID2 is also able to abolish the function of another growth inhibitory protein, p16 (600160), which operates upstream to RB. The Rb-null phenotype is lethal at embryonic day 14.5 because of widespread proliferation, defective differentiation, and apoptosis in the nervous system and hematopoietic precursors. Since Id2 is expressed in these cell types at the time that Rb-null embryos die, Lasorella et al. (2000) hypothesized that if ID2 is a natural target of RB, manifestation of the RB-mutant phenotype might require intact ID2. Disruption of the RB pathway is a hallmark of cancer, and it is widely accepted that normal RB function must be removed in all human tumors. Therefore, Lasorella et al. (2000) set out to determine whether tumor cells deregulate ID2 to bypass the RB pathway. Lasorella et al. (2000) intercrossed Rb and Id2 mutant mice and showed a genetic interaction between Rb and Id2 during development. Id2-Rb double knockout embryos survive to term with minimal or no defects in neurogenesis and hematopoiesis, but they die at birth from severe reduction of muscle tissue. In addition, Lasorella et al. (2000) analyzed the involvement of ID2 in neuroblastoma. Activation of the N-myc protooncogene (190080) in neuroblastoma caused an increase in Id2 to more than the otherwise active, hypophosphorylated Rb in these cells. Lasorella et al. (2000) found that this effect is the result of inappropriate activity of a transcriptional network where Myc transcription factors increase expression of Id2 to bypass the Rb block and drive progression of the cell cycle. Cell cycle progression induced by Myc oncoproteins requires inactivation of Rb by Id2. Thus, a dual connection links Id2 and Rb: during normal cell cycle, Rb prohibits the action of Id2 on its natural targets, but oncogenic activation of the Myc-Id2 transcriptional pathway overrides the tumor-suppressor function of Rb.
Using immunocytochemistry, Wang et al. (2001) showed that rat oligodendrocyte precursor cells express Id2 and Mash1 (100790). They found that overexpression of Id2 inhibits differentiation of rat oligodendrocyte precursor cell cultures. In rat oligodendrocyte precursor cell cultures, they found that Id2 normally translocates out of the nucleus at the onset of differentiation. By culturing purified oligodendrocyte precursor cells from Id2 knockout mice, Wang et al. (2001) determined that absence of Id2 slows proliferation and induces premature oligodendrocyte differentiation in vitro. They concluded that Id2 is a component of the intracellular mechanism controlling the timing of oligodendrocyte differentiation.
Iavarone et al. (2004) showed that Rb-deficient embryos carry profound abnormalities of fetal liver macrophages that prevent physical interactions with erythroblasts. In contrast, wildtype macrophages bind Rb-deficient erythroblasts and lead to terminal differentiation and enucleation. Loss of Id2, a helix-loop-helix protein that mediates the lethality of Rb-deficient embryos, rescues the defects of Rb-deficient fetal liver macrophages. Rb promotes differentiation of macrophages by opposing the inhibitory functions of Id2 on the transcription factor PU.1 (165170), a master regulator of macrophage differentiation. Thus, Rb has a cell-autonomous function in fetal liver macrophages, and restrains Id2 in these cells to implement definitive erythropoiesis.
Li et al. (2005) found that polycystin-2 (PKD2; 173910) overexpression in human embryonic kidney cells led to reduced cell proliferation. They showed that polycystin-2 interacted directly with ID2 and modulated the cell cycle via the ID2-CDKN1A (116899)-CDK2 (116953) pathway. The ID2-polycystin-2 interaction caused sequestration of ID2 in the cytoplasm and required polycystin-1 (PKD1; 601313)-dependent serine phosphorylation of polycystin-2. Kidney epithelial cells from a mouse model of PKD1 showed abnormalities in the cell cycle that could be reversed by RNA interference-mediated inhibition of ID2 mRNA expression.
Lasorella et al. (2006) demonstrated that ID2 interacts with the core subunits of APC/C (see 603462) and CDH1 (192090) in primary neurons. APC/C(CDH1) targets ID2 for degradation through a destruction box motif (D box) that is conserved in ID1 and ID4 (600581). Depletion of CDH1 stabilizes ID proteins in neurons, whereas ID2 D box mutants are impaired for CDH1 binding and remain stable in cells that exit from the cell cycle and contain active APC/C(CDH1). Mutants of the ID2 D box enhance axonal growth in cerebellar granule neurons in vitro and in the context of the cerebellar cortex, and overcome the myelin inhibitory signals for growth. Conversely, activation of bHLH transcription factors induces a cluster of genes with potent axonal inhibitory functions including the gene encoding the NOGO receptor (RTN4R; 605566), a key transducer of myelin inhibition. Degradation of ID2 in neurons permits the accumulation of the NOGO receptor, thereby linking APC/C(CDH1) activity with bHLH target genes for the inhibition of axonal growth. Lasorella et al. (2006) suggested that deregulated ID activity might be useful to reprogram quiescent neurons into the axonal growth mode.
By microdissection of the mouse ventricular conduction system, followed by serial analysis of gene expression (SAGE) of the left bundle branch, Moskowitz et al. (2007) identified Id2 as a conduction system-specific transcript. Analysis of the Id2 promoter showed that conduction system-specific expression of Id2 was dependent on Nkx2.5 (NKX2E; 600584) and Tbx5 (601620). SAGE results indicated that conduction system cells were less differentiated toward cardiac muscle than nonconduction cardiomyocytes. Moskowitz et al. (2007) hypothesized that Id2 may help shift the balance of gene expression from promuscle towards proneural by inhibiting cardiac muscle gene expression in cardiac cells fated to become the ventricular conduction system.
Luo et al. (2016) provided data indicating that PGC1-alpha (604517) suppresses melanoma (155600) metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1-alpha expression inversely correlated with vertical growth in human melanoma specimens. Mechanistically, PGC1-alpha directly increases transcription of ID2, which in turn binds to and inactivates the transcription factor TCF4 (602272). Inactive TCF4 caused downregulation of metastasis-related genes, including integrins that influence invasion and metastasis.
Lee et al. (2016) reported that DYRK1A (600855) and DYRK1B (604556) kinases phosphorylate ID2 on threonine-27 (thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (EGLN2; 606424). ID2 binds to the VHL (608537) ubiquitin ligase complex, displaces VHL-associated cullin-2 (603135), and impairs HIF2-alpha (603349) ubiquitylation and degradation. Phosphorylation of thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2-alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2-alpha activity. Conversely, elevated expression of DYRK1 phosphorylates thr27 of ID2, leading to HIF2-alpha destabilization, loss of glioma stemness, inhibition of tumor growth, and a more favorable outcome for patients with glioblastoma.
Yokota et al. (1999) observed that Id2-deficient mice lacked lymph nodes and Peyer patches. However, their splenic architecture was normal, exhibiting T-cell and B-cell compartments and distinct germinal centers. The authors reported that the cell population that produces lymphotoxins, essential factors for the development of secondary lymphoid organs, is barely detectable in the Id2-deficient intestine. Furthermore, the null mutants showed a greatly reduced population of natural killer (NK) cells, due to an intrinsic defect in NK-cell precursors. Yokota et al. (1999) concluded that Id2 has an essential role in the generation of peripheral lymphoid organs and NK cells.
Fukuyama et al. (2002) found that the mouse nasopharyngeal-associated lymphoid tissue (NALT), which is comparable to the Waldeyer ring in human, was present in Il7r (146661)-, Lta (153440)-, and Ltb (600978)-deficient mice and in aly/aly (see MAP3K14 604655) mice, all of which lack Peyer patches and/or lymph nodes. However, these mice had reduced high endothelial venule NALT-specific markers, and the NALT was reduced in size. B cells, T cells, and dendritic cells accumulated in the NALT of Lta-deficient mice and aly/aly mice, and CD3 (see 186830)-negative/CD4 (186940)-positive/CD45 (PTPRC; 151460)-positive cells were present in Lta-deficient mice. Fukuyama et al. (2002) found that Id2-deficient mice, which lack CD3-negative/CD4-positive/CD45-positive cells, were deficient in NALT. Unlike Lta-deficient mice, the NALT did not expand and remained absent after Id2-deficient mice were immunized with cholera toxin. Transplantation of whole fetal liver or, to a lesser extent, CD3-negative/CD4-positive/CD45-positive cells, restored NALT formation in Id2-deficient mice. Fukuyama et al. (2002) concluded that ID2 and its associated CD3-negative/CD4-positive/CD45-positive cells initiate NALT organogenesis, but additional factors are required for full NALT development.
Sugai et al. (2003) generated mice deficient in Id2. The mice lacked lymph nodes and Peyer patches and had reduced numbers of NK cells, but splenic architecture was normal, exhibiting T- and B-cell compartments and distinct germinal centers. These mice secreted increasing amounts of IgE in sera. Sugai et al. (2003) showed that B cells from the Id2-deficient mice preferentially underwent class switch recombination (CSR) to IgE. The switch was primarily caused by highly augmented E2A (TCF3; 147141) activity. In normal cells, Id2 expression and inhibition of IgE CSR was induced by TGFB1 (190180), suggesting that ID2 acts to maintain low serum concentration of IgE in response to TGFB1.
Hacker et al. (2003) found that, like Tgfb-deficient mice, Id2-deficient mice lacked Langerhans cells, the cutaneous contingent of dendritic cells (DCs). These mice also had reduced amounts of Cd8a (186910)-positive DCs. Microarray and RNA hybridization analyses indicated that TGFB induced ID2 expression in human DC precursors, suggesting that ID2 affects lineage differentiation.
In the developing heart, Id1 (600349), Id2, and Id3 (600277) are detected in the endocardial cushion mesenchyme from embryonic days 10.5 through 16.5, but Id4 (600581) is absent. Fraidenraich et al. (2004) showed that Id1 to Id3 are also expressed in the epicardium and endocardium but are absent in the myocardium. Id1 to Id3 expression becomes confined in the leaflets of the cardiac valves as the atrioventricular endocardial cushion tissue myocardializes. Id1 and Id3 expression persists in the cardiac valves, endocardium, endothelium, and epicardium at postnatal day 7. Fraidenraich et al. (2004) found that double and triple Id knockout embryos displayed severe cardiac defects and died at midgestation. Embryo size was reduced by 10 to 30%. Knockout embryos displayed ventricular septal defects associated with impaired ventricular trabeculation and thinning of the compact myocardium. Trabeculae had disorganized sheets of myocytes surrounded by discontinuous endocardial cell lining. Cell proliferation in the myocardial wall was defective. Fraidenraich et al. (2004) showed that midgestation lethality of embryos was rescued by the injection of 15 wildtype embryonic stem (ES) cells into mutant blastocysts. Myocardial markers altered in Id mutant cells were restored to normal throughout the chimeric myocardium. Intraperitoneal injection of ES cells into female mice before conception also partially rescued the cardiac phenotype with no incorporation of ES cells. Insulin-like growth factor-1 (IGF1; 147440), a long-range secreted factor, in combination with Wnt5a (164975), a locally secreted factor, were thought likely to account for complete reversion of the cardiac phenotype. Fraidenraich et al. (2004) concluded that ES cells have the potential to reverse congenital defects through Id-dependent local and long-range effects in a mammalian embryo.
By selective deletion of both Id2 and Id3 at the pre-T-cell receptor (TCR) and gamma/delta TCR checkpoints in mice, Li et al. (2013) observed a partial block at the pre-TCR checkpoint as well as increased production of innate gamma/delta T cells. In addition, the double deletion resulted in a dramatic increase in invariant NKT (iNKT) cells. Li et al. (2013) proposed that there are opposing roles for ID genes in regulating the alpha/beta and innate gamma/delta lineages. They concluded that there is a dosage-dependent mechanism for ID genes in repressing the fate of innate-like gamma/delta T cells versus iNKT cells during T-cell development.
Fraidenraich, D., Stillwell, E., Romero, E., Wilkes, D., Manova, K., Basson, C. T., Benezra, R. Rescue of cardiac defects in Id knockout embryos by injection of embryonic stem cells. Science 306: 247-252, 2004. [PubMed: 15472070] [Full Text: https://doi.org/10.1126/science.1102612]
Fukuyama, S., Hiroi, T., Yokota, Y., Rennert, P. D., Yanagita, M., Kinoshita, N., Terawaki, S., Shikina, T., Yamamoto, M., Kurono, Y., Kiyono, H. Initiation of NALT organogenesis is independent of the IL-7R, LT-beta-R, and NIK signaling pathways but requires the Id2 gene and CD3-CD4+CD45+ cells. Immunity 17: 31-40, 2002. [PubMed: 12150889] [Full Text: https://doi.org/10.1016/s1074-7613(02)00339-4]
Hacker, C., Kirsch, R. D., Ju, X.-S., Hieronymus, T., Gust, T. C., Kuhl, C., Jorgas, T., Kurz, S. M., Rose-John, S., Yokota, Y., Zenke, M. Transcriptional profiling identifies Id2 function in dendritic cell development. Nature Immun. 4: 380-386, 2003. [PubMed: 12598895] [Full Text: https://doi.org/10.1038/ni903]
Hara, E., Yamaguchi, T., Nojima, H., Ide, T., Campisi, J., Okayama, H., Oda, K. Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J. Biol. Chem. 269: 2139-2145, 1994. [PubMed: 8294468]
Iavarone, A., Garg, P., Lasorella, A., Hsu, J., Israel, M. A. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev. 8: 1270-1284, 1994. [PubMed: 7926730] [Full Text: https://doi.org/10.1101/gad.8.11.1270]
Iavarone, A., King, E. R., Dai, X.-M., Leone, G., Stanley, E. R., Lasorella, A. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 432: 1040-1045, 2004. [PubMed: 15616565] [Full Text: https://doi.org/10.1038/nature03068]
Lasorella, A., Iavarone, A., Israel, M. A. Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Molec. Cell. Biol. 16: 2570-2578, 1996. [PubMed: 8649364] [Full Text: https://doi.org/10.1128/MCB.16.6.2570]
Lasorella, A., Noseda, M., Beyna, M., Yokota, Y., Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407: 592-598, 2000. Note: Erratum: 408: 498 only, 2000. [PubMed: 11034201] [Full Text: https://doi.org/10.1038/35036504]
Lasorella, A., Stegmuller, J., Guardavaccaro, D., Liu, G., Carro, M. S., Rothschild, G., de la Torre-Ubieta, L., Pagano, M., Bonni, A., Iavarone, A. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442: 471-474, 2006. [PubMed: 16810178] [Full Text: https://doi.org/10.1038/nature04895]
Lee, S. B., Frattini, V., Bansal, M., Castano, A. M., Sherman, D., Hutchinson, K., Bruce, J. N., Califano, A., Liu, G., Cardozo, T., Iavarone, A., Lasorella, A. An ID2-dependent mechanism for VHL inactivation in cancer. Nature 529: 172-177, 2016. [PubMed: 26735018] [Full Text: https://doi.org/10.1038/nature16475]
Li, J., Wu, D., Jiang, N., Zhuang, Y. Combined deletion of Id2 and Id3 genes reveals multiple roles for E proteins in invariant NKT cell development and expansion. J. Immun. 191: 5052-5064, 2013. [PubMed: 24123680] [Full Text: https://doi.org/10.4049/jimmunol.1301252]
Li, X., Luo, Y., Starremans, P. G., McNamara, C. A., Pei, Y., Zhou, J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nature Cell Biol. 7: 1202-1212, 2005. Note: Erratum: Nature Cell Biol. 8: 100 only, 2006. [PubMed: 16311606] [Full Text: https://doi.org/10.1038/ncb1326]
Luo, C., Lim, J.-H., Lee, Y., Granter, S. R., Thomas, A., Vazquez, F., Widlund, H. R., Puigserver, P. A PGC1-alpha-mediated transcriptional axis suppresses melanoma metastasis. Nature 537: 422-426, 2016. [PubMed: 27580028] [Full Text: https://doi.org/10.1038/nature19347]
Mathew, S., Chen, W., Murty, V. V. V. S., Benezra, R., Chaganti, R. S. K. Chromosomal assignment of human ID1 and ID2 genes. Genomics 30: 385-387, 1995. [PubMed: 8586447] [Full Text: https://doi.org/10.1006/geno.1995.0037]
Moskowitz, I. P. G., Kim, J. B., Moore, M. L., Wolf, C. M., Peterson, M. A., Shendure, J., Nobrega, M. A., Yokota, Y., Berul, C., Izumo, S., Seidman, J. G., Seidman, C. E. A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell 129: 1365-1376, 2007. [PubMed: 17604724] [Full Text: https://doi.org/10.1016/j.cell.2007.04.036]
Sugai, M., Gonda, H., Kusunoki, T., Katakai, T., Yokota, Y., Shimizu, A. Essential role of Id2 in negative regulation of IgE class switching. Nature Immun. 4: 25-30, 2003. [PubMed: 12483209] [Full Text: https://doi.org/10.1038/ni874]
Wang, S., Sdrulla, A., Johnson, J. E., Yokota, Y., Barres, B. A. A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development. Neuron 29: 603-614, 2001. [PubMed: 11301021] [Full Text: https://doi.org/10.1016/s0896-6273(01)00237-9]
Yokota, Y., Mansouri, A., Mori, S., Sugawara, S., Adachi, S., Nishikawa, S.-I., Gruss, P. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397: 702-706, 1999. [PubMed: 10067894] [Full Text: https://doi.org/10.1038/17812]