Download Gene Section NOTCH2 (Notch homolog 2 (Drosophila)) Atlas of Genetics and Cytogenetics

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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.
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