Atlas of Genetics and Cytogenetics in Oncology and Haematology
NOTCH2 (Notch homolog 2 (Drosophila))
| Identity |
| Other names | AGS2 |
| hN2 | |
| HGNC | NOTCH2 |
| Location | 1p12 |
| DNA/RNA |
 | |
| Description | 34 exons |
| Transcription | 7860 bp |
| Protein |
 | |
| A. : 2472 AA, 265.4 KD. LNR: Lin/Notch repeats (light blue); TM: transmembrane; OPA: glutamine-rich region; PEST sequence Dark blue: Epidermal Growth Factor repeats Light red: ankyrin repeats Dark red: Nuclear localization signal B. : Notch activation diagram | |
| Description | This gene encodes a member of the Notch family. Members of this family are Type1 transmembrane receptors and share structural characteristics represented in the diagram. The conserved domains include 36 EGF repeats and 3 lin/Notch Repeats (LNR) in the extracellular domain, 7 Ankyrin repeats, 2 different nuclear localization domains and 1 OPA/PEST region conform the intracellular domain. The Notch2 gene is transcribed and translated as a single inactive protein. This protein is cleaved by a furin-like convertase in the trans-golgi network before it reaches the plasma membrane to yield an active form. Cleavage results in a C-terminal fragment and a N-terminal fragment, linked by disulfide bridges. Following ligand binding, it is first cleaved by ADAM17 metallopeptidase to yield a membrane-associated intermediate fragment. This fragment is then cleaved by presenilin dependent gamma-secretase to release a Notch-derived peptide containing the intracellular domain from the membrane (see Notch activation diagram). Protein modifications: |
| Expression | Expressed in the brain, heart, kidney, spleen (hematopoietic cells,T-cells, B-cells and mast cells), lung, intestine, skeletal muscle and liver (hepatic cells and bile duct cells), ameloblasts. |
| Localisation | Type I membrane protein. Following proteolytical processing it is translocated to the nucleus. |
| Function | Physiological receptor for membrane-bound ligands jagged1, jagged2 and delta1 to regulate cell-fate determination. Upon ligand activation, Notch intracellular domain forms a transcriptional activator complex with RBP-j kappa and Mastermind proteins and activates genes of the hairy/enhancer of split (hes) family. Notch2 behaves very similar to Notch1 at the biochemical level, and in fact, C-terminal intracellular region of Notch1 can functionally replace that of Notch2 in vivo. However specific functions, specific expression patterns and embryonic lethality of single mutant mice indicate that both proteins are not redundant. Biological functions strictly associated to Notch2 are: |
| Homology | Degree of amino acid identity between Notch1 and Notch2 proteins: overall, 56%; EGF-like repeats, 58%; LNR,58%; CDC10, 76% and PEST, 79%. |
| Mutations |
| Germinal | Two different mutations segregating in two families affected by Alagille syndrome: One mutation results in partial deletion of the intracellular domain including 4 ankyrin repeats, the second mutation affects EGF repeat 11. |
| Implicated in |
| Entity | Alagille syndrome (AGS) |
| Disease | Alagille syndrome (AGS) is a dominant multisystem disorder defined clinically by bile duct paucity and cholestasis in association with cardiac, skeletal and ophthalmologic manifestations with less-frequent clinical involvement of renal and vascular systems. 94% of affected individuals have mutations in the Jagged1 gene. |
| Oncogenesis | Notch2 intracellular domain (active Notch2) has neoplastic transformation capacities. |
| Entity | B-Cell Chronic Lymphoblastic Leukemia (B-CLL). |
| Oncogenesis | Function: upregulation of CD23, which has been correlated with high cell viability and inhibition of apoptosis in B-CLL. |
| Entity | Embryonal brain tumors, medulloblastoma |
| Prognosis | Target gene hes1 expression correlates with shorter patient survival. |
| Oncogenesis | Loss of heterozygosity of Notch2 results in positive survival of Oligodendrioma and glioblastoma. Amplification in 15% of 40 analyzed embryonal brain tumors. |
| Entity | Melanoma |
| Oncogenesis | Amplification of 1p12 in melanoma cell lines |
| Entity | Lung carcinoma |
| Oncogenesis | Amplification in 9 of 12 samples of squamous lung carcinoma. |
| Entity | Breast carcinoma |
| Oncogenesis | Putative role of Notch2 as tumor suppressor since upregulation of its expression is associated with survival, and activated Notch2 induces apoptosis in breast cancer xenografts. |
| External links |
| Bibliography |
| Notch2: a second mammalian Notch gene. |
| Weinmaster G, Roberts VJ, Lemke G. |
| Development. 1992 Dec;116(4):931-41. |
| PMID 1295745 |
| Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. |
| Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S, Bishop JM. |
| Mol Cell Biol. 1997 Nov;17(11):6265-73. |
| PMID 9343387 |
| Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. |
| Bigas A, Martin DI, Milner LA. |
| Mol Cell Biol. 1998 Apr;18(4):2324-33. |
| PMID 9528802 |
| Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. |
| Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman JR, Tsujimoto Y. |
| Development. 1999 Aug;126(15):3415-24. |
| PMID 10393120 |
| Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and |
| Shimizu K, Chiba S, Hosoya N, Kumano K, Saito T, Kurokawa M, Kanda Y, Hamada Y, Hirai H. |
| Mol Cell Biol. 2000 Sep;20(18):6913-22. |
| PMID 10958687 |
| Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis. |
| Saxena MT, Schroeter EH, Mumm JS, Kopan R. |
| J Biol Chem. 2001 Oct 26;276(43):40268-73. |
| PMID 11518718 |
| Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different |
| Shimizu K, Chiba S, Saito T, Kumano K, Takahashi T, Hirai H. |
| J Biol Chem. 2001 Jul 13;276(28):25753-8. |
| PMID 11346656 |
| Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. |
| Hubmann R, Schwarzmeier JD, Shehata M, Hilgarth M, Duechler M, Dettke M, Berger R. |
| Blood. 2002 May 15;99(10):3742-7. |
| PMID 11986231 |
| Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt |
| Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A. |
| J Biol Chem. 2003 Aug 22;278(34):32227-35. |
| PMID 12794074 |
| Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. |
| Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K, Yamaguchi T, Yamamoto G, Seo S, Kumano K, Nakagami-Yamaguchi E, Hamada Y, Aizawa S, Hirai H. |
| Immunity. 2003 May;18(5):675-85. |
| PMID 12753744 |
| Activated Notch2 potentiates CD8 lineage maturation and promotes the selective development of B1 B cells. |
| Witt CM, Hurez V, Swindle CS, Hamada Y, Klug CA. |
| Mol Cell Biol. 2003 Dec;23(23):8637-50. |
| PMID 14612407 |
| Notch1 and notch2 have opposite effects on embryonal brain tumor growth. |
| Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A, Eberhart CG. |
| Cancer Res. 2004 Nov 1;64(21):7787-93. |
| PMID 15520184 |
| Involvement of multiple developmental genes on chromosome 1p in lung tumorigenesis. |
| Garnis C, Campbell J, Davies JJ, Macaulay C, Lam S, Lam WL. |
| Hum Mol Genet. 2005 Feb 15;14(4):475-82. |
| PMID 15615770 |
| Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis. |
| Pan Y, Liu Z, Shen J, Kopan R. |
| Dev Biol. 2005 Oct 15;286(2):472-82. |
| PMID 16169548 |
| Loss of NOTCH2 positively predicts survival in subgroups of human glial brain tumors. |
| Boulay JL, Miserez AR, Zweifel C, Sivasankaran B, Kana V, Ghaffari A, Luyken C, Sabel M, Zerrouqi A, Wasner M, Van Meir E, Tolnay M, Reifenberger G, Merlo A. |
| PLoS ONE. 2007 Jun 27;2(6):e576. |
| PMID 17593975 |
| Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. |
| Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, McMahon AP, Kopan R. |
| Development. 2007 Feb;134(4):801-11. |
| PMID 17229764 |
| Notch2 is required for formation of the placental circulatory system, but not for cell-type specification in the |
| Hamada Y, Hiroe T, Suzuki Y, Oda M, Tsujimoto Y, Coleman JR, Tanaka S. |
| Differentiation. 2007 Mar;75(3):268-78. |
| PMID 17359302 |
| Synergism between NF-kappa B1/p50 and Notch2 during the development of marginal zone B lymphocytes. |
| Moran ST, Cariappa A, Liu H, Muir B, Sgroi D, Boboila C, Pillai S. |
| J Immunol. 2007 Jul 1;179(1):195-200. |
| PMID 17579038 |
| Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. |
| O’Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, León R, Toher J, Mouta-Bellum C, Friesel RE, Liaw L. |
| Am J Pathol. 2007 Sep;171(3):1023-36. |
| PMID 17675579 |
| The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development. |
| Wu L, Maillard I, Nakamura M, Pear WS, Griffin JD. |
| Blood. 2007 Nov 15;110(10):3618-23. |
| PMID 17699740 |
| 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 WG. |
| Int J Mol Med. 2004 Nov;14(5):779-86. |
| PMID 15492845 |
| Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. |
| O’Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, León R, Toher J, Mouta-Bellum C, Friesel RE, Liaw L. |
| Am J Pathol. 2007 Sep;171(3):1023-36. |
| PMID 17675579 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 03-2008 | Anna Bigas, Lluis Espinosa |
| Instituto de Investigación Biomédica de Bellvitge, IDIBELL, Barcelona, Spain |
| Citation |
| This paper should be referenced as such : |
| Bigas A, Espinosa L . NOTCH2 (Notch homolog 2 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. March 2008 . URL : http://AtlasGeneticsOncology.org/Genes/NOTCH2ID41556ch1p12.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Sep 29 18:43:19 2008 |
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