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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review NOTCH2 (Notch homolog 2 (Drosophila)) Anna Bigas, Lluis Espinosa Instituto de Investigación Biomédica de Bellvitge, IDIBELL, Barcelona, Spain (AB,LE) Published in Atlas Database: March 2008 Online updated version : http://AtlasGeneticsOncology.org/Genes/NOTCH2ID41556ch1p12.html DOI: 10.4267/2042/44380 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Other names: AGS2; hN2 HGNC (Hugo): NOTCH2 Location: 1p12 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 Nterminal fragment, linked by disulfide bridges. Following ligand binding, it is first cleaved by ADAM17 metallopeptidase to yield a membraneassociated 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: DNA/RNA Description 34 exons. Transcription 7860 bp. Protein 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) Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1) 20 NOTCH2 (Notch homolog 2 (Drosophila)) Bigas A, Espinosa L 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 lung, intestine, skeletal muscle and liver (hepatic cells and bile duct cells), ameloblasts. Phosphorylation: Different phosphorylation pro-cessses are important for regulating Notch2 activity. Only GSK3beta has been found to phos-phorylate Notch2 in 32D-myeloid cells. Glycosylation: fringe glycosyl-transferases modify the extracellular domain of Notch2 by glycosylation. Localisation Expression Function Expressed in the brain, heart, kidney, spleen (hematopoietic cells,T-cells, B-cells and mast cells), Physiological receptor for membrane-bound ligands jagged1, jagged2 and delta1 to regulate cell-fate Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1) Type I membrane protein. Following proteolytical processing it is translocated to the nucleus. 21 NOTCH2 (Notch homolog 2 (Drosophila)) Bigas A, Espinosa L 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 expres-sion patterns and embryonic lethality of single mutant mice indicate that both proteins are not redundant. Biological functions strictly associated to Notch2 are: Development of kidney (proximal nephron struc-tures: podocytes and proximal convoluted tubules). B-cell differentiation: involved in the final stages of Bcell maturation at the marginal zone of the spleen and expression of CD23 in B-CLL (B-Cell Chronic Lymphoblastic leukaemia). T-cell maturation: later stages of T cell development, induction of CD8+ cells. Notch2 is also required for formation of the placental circulatory system. 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. Melanoma Oncogenesis Amplification of 1p12 in melanoma cell lines Lung carcinoma Oncogenesis Amplification in 9 of 12 samples of squamous lung carcinoma. 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. Homology Degree of amino acid identity between Notch1 and Notch2 proteins: overall, 56%; EGF-like repeats, 58%; LNR,58%; CDC10, 76% and PEST, 79%. References Mutations Weinmaster G, Roberts VJ, Lemke G. Notch2: a second mammalian Notch gene. Development. 1992 Dec;116(4):93141 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. Capobianco AJ, Zagouras P, Blaumueller CM, ArtavanisTsakonas S, Bishop JM. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Mol Cell Biol. 1997 Nov;17(11):6265-73 Bigas A, Martin DI, Milner LA. Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Mol Cell Biol. 1998 Apr;18(4):2324-33 Implicated in Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman JR, Tsujimoto Y. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development. 1999 Aug;126(15):3415-24 Alagille syndrome (AGS) Disease Alagille syndrome (AGS) is a dominant multi-system 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. Shimizu K, Chiba S, Hosoya N, Kumano K, Saito T, Kurokawa M, Kanda Y, Hamada Y, Hirai H. Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2. Mol Cell Biol. 2000 Sep;20(18):6913-22 Saxena MT, Schroeter EH, Mumm JS, Kopan R. Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis. J Biol Chem. 2001 Oct 26;276(43):40268-73 Shimizu K, Chiba S, Saito T, Kumano K, Takahashi T, Hirai H. Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation. J Biol Chem. 2001 Jul 13;276(28):25753-8 B-Cell Chronic Lymphoblastic Leukemia (B-CLL) Hubmann R, Schwarzmeier JD, Shehata M, Hilgarth M, Duechler M, Dettke M, Berger R. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002 May 15;99(10):3742-7 Oncogenesis Function: upregulation of CD23, which has been correlated with high cell viability and inhibition of apoptosis in B-CLL. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1) 22 NOTCH2 (Notch homolog 2 (Drosophila)) Bigas A, Espinosa L Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta downregulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem. 2003 Aug 22;278(34):32227-35 positively predicts survival in subgroups of human glial brain tumors. PLoS One. 2007 Jun 27;2(6):e576 Cheng HT, Kim M, Valerius MT, Surendran K, SchusterGossler K, Gossler A, McMahon AP, Kopan R. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development. 2007 Feb;134(4):801-11 Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K, Yamaguchi T, Yamamoto G, Seo S, Kumano K, NakagamiYamaguchi E, Hamada Y, Aizawa S, Hirai H. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity. 2003 May;18(5):675-85 Hamada Y, Hiroe T, Suzuki Y, Oda M, Tsujimoto Y, Coleman JR, Tanaka S. Notch2 is required for formation of the placental circulatory system, but not for cell-type specification in the developing mouse placenta. Differentiation. 2007 Mar;75(3):268-78 Witt CM, Hurez V, Swindle CS, Hamada Y, Klug CA. Activated Notch2 potentiates CD8 lineage maturation and promotes the selective development of B1 B cells. Mol Cell Biol. 2003 Dec;23(23):8637-50 Moran ST, Cariappa A, Liu H, Muir B, Sgroi D, Boboila C, Pillai S. Synergism between NF-kappa B1/p50 and Notch2 during the development of marginal zone B lymphocytes. J Immunol. 2007 Jul 1;179(1):195-200 Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A, Eberhart CG. Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res. 2004 Nov 1;64(21):7787-93 O'Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, León R, Toher J, Mouta-Bellum C, Friesel RE, Liaw L. Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. Am J Pathol. 2007 Sep;171(3):1023-36 Parr C, Watkins G, Jiang WG. The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med. 2004 Nov;14(5):779-86 O'Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, León R, Toher J, Mouta-Bellum C, Friesel RE, Liaw L. Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. Am J Pathol. 2007 Sep;171(3):1023-36 Garnis C, Campbell J, Davies JJ, Macaulay C, Lam S, Lam WL. Involvement of multiple developmental genes on chromosome 1p in lung tumorigenesis. Hum Mol Genet. 2005 Feb 15;14(4):475-82 Wu L, Maillard I, Nakamura M, Pear WS, Griffin JD. The transcriptional coactivator Maml1 is required for Notch2mediated marginal zone B-cell development. Blood. 2007 Nov 15;110(10):3618-23 Pan Y, Liu Z, Shen J, Kopan R. Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis. Dev Biol. 2005 Oct 15;286(2):472-82 This article should be referenced as such: 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. Loss of NOTCH2 Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1) Bigas A, Espinosa L. NOTCH2 (Notch homolog 2 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1):20-23. 23