| Literature References | 1. KOPAN, R. AND ILAGAN, M.
The canonical notch signaling pathway: unfolding the activation mechanism.
CELL 137 216-233 (2009).
2. ARTAVANIS-TSAKONAS, S., RAND, M.D. AND LAKE, R.J.
Notch signaling: cell fate control and signal integration in development.
SCIENCE 284 770-776 (1999).
3. HARTMANN, D., DE STROOPER, B., SERNEELS. L., CRAESSAERTS, K.,
HERREMAN, A., ANNAERT, W., UMANS, L., LUBKE, T., LENA ILLERT, A.,
VON FIGURA, K. AND SAFTIG, P.
The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling
but not for alpha-secretase activity in fibroblasts.
HUM.MOL.GENET. 11 2615-2624 (2002).
4. DE STROOPER, B., ANNAERT, W., CUPERS, P., SAFTIG, P., CRAESSAERTS, K.,
MUMM, J.S., SCHROETER, E.H., SCHRIJVERS, V., WOLFE, M.S., RAY, W.J.,
GOATE, A.AND KOPAN, R.
A presenilin-1-dependent gamma-secretase-like protease mediates release of
Notch intracellular domain.
NATURE 398 518-522 (1999).
5. WU, L., ASTER, J.C., BLACKLOW, S.C., LAKE, R., ARTAVANIS-TSAKONAS, S.,
AND GRIFFIN, J.D.
MAML1, a human homologue of Drosophila mastermind, is a transcriptional
co-activator for NOTCH receptors.
NAT.GENET. 26 484-489 (2000).
6. GRIDLEY, T.
Notch signaling and inherited disease syndromes.
HUM.MOL.GENET. 1 R9-R13 (2003).
7. LOUVI, A. AND ARTAVANIS-TSAKONAS, S.
Notch signalling in vertebrate neural development.
NAT.REV.NEUROSCI. 7 93-102 (2006).
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| Documentation | Notch cell surface receptors are large, single-pass type-1 transmembrane
proteins found in a diverse range of metazoan species, from human to
Caenorhabditis species. The fruit fly, Drosophila melanogaster, possesses
only one Notch protein, whereas in C.elegans, two receptors have been found;
by contrast, four Notch paralogues (designated N1-4) have been identified in
mammals, playing both unique and redundant roles.
The hetero-oligomer Notch comprises a large extracellular domain (ECD),
containing 10-36 tandem Epidermal Growth Factor (EFG)-like repeats, which
are involved in ligand interactions; a negative regulatory region,
including three cysteine-rich Lin12-Notch Repeats (LNR); a single trans-
membrane domain (TM); a small intracellular domain (ICD), which includes a
RAM (RBPjk-association module) domain; six ankyrin repeats (ANK), which are
involved in protein-protein interactions; and a PEST domain. Drosophila
Notch also contains an OPA domain [1].
Notch signalling is an evolutionarily conserved pathway involved in a wide
variety of developmental processes, including adult homeostasis and stem
cell maintainance, cell proliferation and apoptosis [2]. Notch is activated
by a range of ligands - the so-called DSL ligands (Delta/Seratte/LAG-2).
Activation is also mediated by a sequence of proteolytic events: ligand
binding leads to cleavage of Notch by ADAM proteases [3] at site 2 (S2) and
presenilin-1/g-secretase at sites 3 (S3)and 4 (S4) [4].The last cleavage
releases the Notch intracellular part of the protein (NICD) from the
membrane and, upon release, the NICD translocates to the nucleus where it
associates with a CBF1/RBJk/Su(H)/Lag1 (CSL) family of DNA-binding proteins.
The subsequent recruitment of a co-activator mastermind like (MAML1) protein
[5] promotes transcriptional activation of Notch target genes: well
established Notch targets are the Hes and Hey gene families.
Aberrant Notch function and signalling has been associated with a number of
human disorders, including Allagile syndrome, spondylocostal dysostosis,
aortic valve disease, CADASIL (Cerebral Autosomal Dominant Arteriopathy with
Subcortical Infarcts and Leukoencephalopathy), and T-cell Acute Lympho-
blastic Leukemia (T-ALL); it has also been implicated in various human
carcinomas [6,7].
Notch 2 has a widespread expression pattern. It is expressed in a number of
tissues, including brain, heart, kidney, lung, teeth, skeletal muscle and
liver.
NOTCH2 is a 4-element fingerprint that provides a signature for neurogenic
locus Notch protein 2. The fingerprint was derived from an initial alignment
of 5 sequences: the motifs were drawn from conserved regions spanning
virtually the full alignment length - motif 1 lies in a conserved area
C-terminal to the LNR region; motif 2 lies in a conserved section N-terminal
to the TM domain; motif 3 resides in a region C-terminal to the ankyrin
repeats; and motif 4 resides in a region N-terminal to the PEST domain. Two
iterations on SPTR57_40f were required to reach convergence, at which point
a true set comprising 3 sequences was identified. Two partial matches were
also found, both Notch 2 sequences that are missing parts of the sequence
bearing the first 2 motifs.
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