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Gene Review

NOTCH2  -  notch 2

Homo sapiens

Synonyms: AGS2, HJCYS, Neurogenic locus notch homolog protein 2, Notch 2, hN2
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Disease relevance of NOTCH2


High impact information on NOTCH2

  • Increased Notch1 signaling, but not Notch2, causes a dramatic down-modulation of HPV-driven transcription of the E6/E7 viral genes, through suppression of AP-1 activity by up-regulation of the Fra-1 family member and decreased c-Fos expression [8].
  • We previously reported the isolation from a thymic tumor of a feline leukemia virus that had transduced a fragment of the Notch2 gene [9].
  • Here we present evidence that a nuclear form of Notch2 corresponding to the biologically active intracellular domain (N2ICD) is expressed from this recombinant retrovirus through internal ribosome entry [9].
  • In addition, new evidence points to a requirement for Notch2 in the development of marginal zone B cells [10].
  • Furthermore, ectopic expression of DVL1, LRP8 and Notch2 in malignant lung tissue validates the biological impact of these genetic alterations [11].

Chemical compound and disease context of NOTCH2


Biological context of NOTCH2


Anatomical context of NOTCH2

  • Notch-1 and Notch-2 showed a transient induction after 2 days and a decrease after 7 days in osteoblasts and after 28 days in SaOS-2 cells [17].
  • Notch-2 was only seen occasionally within the developing cortex and spinal cord [18].
  • RESULTS: Notch2 and Notch4 were expressed in limited areas in a few samples or in small blood vessels, respectively [19].
  • Transforming growth factor beta-1, which stimulates odontoblast differentiation and hard tissue formation after dental injury, downregulated Notch2 expression in cultured human dental slices, in vitro [20].
  • During the earlier stages of tooth development, the Notch2 protein was expressed in the epithelium, but was absent from proliferating cells of the inner enamel epithelium [20].

Associations of NOTCH2 with chemical compounds

  • Supershift assays revealed that the nuclear form of Notch2 is a component of C1 in B-CLL cells, supporting a model in which NotchIC activates transcription by binding to CBF1 tethered to DNA [21].
  • Here we report that Notch2 acts non-redundantly to control the processes of nephron segmentation through an Rbp-J-dependent process [22].
  • We identify three specific phosphorylation sites in the Notch2 serine/threonine-rich domain that are dependent on GSK-3 beta activity [23].
  • It is thus suggested that the cysteine-rich domain of Tat plays a role in the interaction between the Tat and either Notch2 or the epithelin/granulin domains, both of which exhibit EGF-like-repeat-imposed spatial conformation [12].
  • Positive staining for Notch1, Notch 2 in hyperoxia group was much lower than those in room air group at all time points (P < 0. 01, P < 0.05), but compared with the controls, the hyperoxia group showed higher expression of Notch3 (P > 0.05) [24].

Physical interactions of NOTCH2

  • Coimmunoprecipitation experiments show that full-length Notch2 binds more efficiently than intracellular Notch2 to GSK-3 beta [23].

Enzymatic interactions of NOTCH2


Regulatory relationships of NOTCH2

  • However, the decrease in Jagged1-triggered Notch2 signaling by mFng was again greater than that by lFng [25].
  • Genetic analysis reveals that only Notch2 is required for the differentiation of proximal nephron structures (podocytes and proximal convoluted tubules) despite the presence of activated Notch1 in the nuclei of putative proximal progenitors [22].
  • Activation of Notch2 was down-regulated by CHSY1 siRNA treatment [26].
  • Overexpression of active Notch2 inhibited TGF-beta1-induced expression of alpha-SMA and collagen I [27].
  • Furthermore, we found Notch3 was counter-regulated by Notch2 in C2C12 cells [27].

Other interactions of NOTCH2

  • Although both manic fringe (mFng) and lunatic fringe (lFng) decreased the binding of Jagged1 to Notch2 and not that of Delta1, the decrease by mFng was greater in degree than that by lFng [25].
  • Therefore, Notch-1 may possess tumour-promoting functions, while Notch-2 could play a tumour-suppressive role in human breast cancer [4].
  • Neither Notch-2, nor -3 showed overlap with either PS1 or PS2 immunoreactivity [18].
  • The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated [28].
  • Notch3 mRNA was increased significantly, while Notch1 mRNA was decreased compared to controls, and expression of Notch2 was similar to that of control [29].

Analytical, diagnostic and therapeutic context of NOTCH2




  1. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. McDaniell, R., Warthen, D.M., Sanchez-Lara, P.A., Pai, A., Krantz, I.D., Piccoli, D.A., Spinner, N.B. Am. J. Hum. Genet. (2006) [Pubmed]
  2. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Isidor, B., Lindenbaum, P., Pichon, O., Bézieau, S., Dina, C., Jacquemont, S., Martin-Coignard, D., Thauvin-Robinet, C., Le Merrer, M., Mandel, J.L., David, A., Faivre, L., Cormier-Daire, V., Redon, R., Le Caignec, C. Nat. Genet. (2011) [Pubmed]
  3. Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation. Hsieh, J.J., Nofziger, D.E., Weinmaster, G., Hayward, S.D. J. Virol. (1997) [Pubmed]
  4. The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Parr, C., Watkins, G., Jiang, W.G. Int. J. Mol. Med. (2004) [Pubmed]
  5. Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Fan, X., Mikolaenko, I., Elhassan, I., Ni, X., Wang, Y., Ball, D., Brat, D.J., Perry, A., Eberhart, C.G. Cancer Res. (2004) [Pubmed]
  6. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Massi, D., Tarantini, F., Franchi, A., Paglierani, M., Di Serio, C., Pellerito, S., Leoncini, G., Cirino, G., Geppetti, P., Santucci, M. Mod. Pathol. (2006) [Pubmed]
  7. Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. O'Neill, C.F., Urs, S., Cinelli, C., Lincoln, A., Nadeau, R.J., León, R., Toher, J., Mouta-Bellum, C., Friesel, R.E., Liaw, L. Am. J. Pathol. (2007) [Pubmed]
  8. Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Talora, C., Sgroi, D.C., Crum, C.P., Dotto, G.P. Genes Dev. (2002) [Pubmed]
  9. Evidence that an IRES within the Notch2 coding region can direct expression of a nuclear form of the protein. Lauring, A.S., Overbaugh, J. Mol. Cell (2000) [Pubmed]
  10. Notch signaling in lymphocyte development and function. Robey, E.A., Bluestone, J.A. Curr. Opin. Immunol. (2004) [Pubmed]
  11. Involvement of multiple developmental genes on chromosome 1p in lung tumorigenesis. Garnis, C., Campbell, J., Davies, J.J., Macaulay, C., Lam, S., Lam, W.L. Hum. Mol. Genet. (2005) [Pubmed]
  12. The Tat protein of the caprine arthritis encephalitis virus interacts with the Notch2 EGF-like repeats and the epithelin/granulin precursor. Shoham, N., Cohen, L., Gazit, A., Yaniv, A. Intervirology (2003) [Pubmed]
  13. Persistent expression of notch2 delays gonadotrope differentiation. Raetzman, L.T., Wheeler, B.S., Ross, S.A., Thomas, P.Q., Camper, S.A. Mol. Endocrinol. (2006) [Pubmed]
  14. The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation. Larsson, C., Lardelli, M., White, I., Lendahl, U. Genomics (1994) [Pubmed]
  15. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Nefedova, Y., Cheng, P., Alsina, M., Dalton, W.S., Gabrilovich, D.I. Blood (2004) [Pubmed]
  16. Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2. Duechler, M., Shehata, M., Schwarzmeier, J.D., Hoelbl, A., Hilgarth, M., Hubmann, R. Leukemia (2005) [Pubmed]
  17. Differential expression of Notch genes in human osteoblastic cells. Schnabel, M., Fichtel, I., Gotzen, L., Schlegel, J. Int. J. Mol. Med. (2002) [Pubmed]
  18. Distribution of presenilin 1 and 2 and their relation to Notch receptors and ligands in human embryonic/foetal central nervous system. Kostyszyn, B., Cowburn, R.F., Seiger, A., Kjaeldgaard, A., Sundström, E. Brain Res. Dev. Brain Res. (2004) [Pubmed]
  19. Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis. Yabe, Y., Matsumoto, T., Tsurumoto, T., Shindo, H. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. (2005) [Pubmed]
  20. Notch2 protein distribution in human teeth under normal and pathological conditions. Mitsiadis, T.A., Roméas, A., Lendahl, U., Sharpe, P.T., Farges, J.C. Exp. Cell Res. (2003) [Pubmed]
  21. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Hubmann, R., Schwarzmeier, J.D., Shehata, M., Hilgarth, M., Duechler, M., Dettke, M., Berger, R. Blood (2002) [Pubmed]
  22. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Cheng, H.T., Kim, M., Valerius, M.T., Surendran, K., Schuster-Gossler, K., Gossler, A., McMahon, A.P., Kopan, R. Development (2007) [Pubmed]
  23. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. Espinosa, L., Inglés-Esteve, J., Aguilera, C., Bigas, A. J. Biol. Chem. (2003) [Pubmed]
  24. Relationship between Notch receptors and hyperoxia-induced lung injury in newborn rats. Zhang, Q., Chang, L., Liu, H., Rong, Z., Chen, H. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. (2005) [Pubmed]
  25. Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation. Shimizu, K., Chiba, S., Saito, T., Kumano, K., Takahashi, T., Hirai, H. J. Biol. Chem. (2001) [Pubmed]
  26. Chondroitin synthase 1 is a key molecule in myeloma cell-osteoclast interactions. Yin, L. J. Biol. Chem. (2005) [Pubmed]
  27. Notch2 negatively regulates myofibroblastic differentiation of myoblasts. Ono, Y., Sensui, H., Okutsu, S., Nagatomi, R. J. Cell. Physiol. (2007) [Pubmed]
  28. Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma. Trøen, G., Nygaard, V., Jenssen, T.K., Ikonomou, I.M., Tierens, A., Matutes, E., Gruszka-Westwood, A., Catovsky, D., Myklebost, O., Lauritzsen, G., Hovig, E., Delabie, J. The Journal of molecular diagnostics : JMD. (2004) [Pubmed]
  29. Effects of sulfated hyaluronan on keratinocyte differentiation and Wnt and Notch gene expression. Nagira, T., Nagahata-Ishiguro, M., Tsuchiya, T. Biomaterials (2007) [Pubmed]
  30. Generation of new Notch2 mutant alleles. McCright, B., Lozier, J., Gridley, T. Genesis (2006) [Pubmed]
  31. Analysis of gene expression patterns and chromosomal changes associated with aging. Geigl, J.B., Langer, S., Barwisch, S., Pfleghaar, K., Lederer, G., Speicher, M.R. Cancer Res. (2004) [Pubmed]
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