● Enzyme Number (IUBMB):
EC 220.127.116.11, EC 18.104.22.168
2555 amino acids; about 273 kDa
The protein encoded by NOTCH1 functions as
a receptor for membrane-bound ligands of the Jagged and Delta-like families. It
is involved in cell-fate determination, implementation of differentiation, proliferation
and apoptotic programs.
Notch1 mutations play a dual role in
carcinogenesis as either a tumor suppressor or an oncogene. The role of NOTCH1
within and between cells depends on signal strength, timing, cell type, and
Altered NOTCH1 is a causative factor in
the development of T-cell acute lymphoblastic leukemia and lymphoma (T-ALL). It
is notably involved in T-ALL following translocation t(7;9)(q34;q34.3),leading to the fusion gene NOTCH1-TRB@, in
which the 3' portion of NOTCH1 is juxtaposed with the T cell receptor β (TRB@) locus. This leads to
expression of truncated NOTCH1 transcripts and consequent production of
dominant active, ligand-independent forms of the NOTCH1 receptor, causing
T-ALL. Less than 1% of human T-ALLs exhibit the t(7;9) translocation, however,
activating mutations in NOTCH1 independent of t(7;9) have been identified in
more than 50% of human T-ALL.
Somatic point mutations have been found in
tumors of haematopoietic and lymphoid tissue (up to 20%), oesophagus and upper
aerodigestive tract, CNS, large intestine, lung, pancreas, breast. Most
mutation events are substitution, with hot spots corresponding to amino acids 1575-1601.
References (open access):
The role of NOTCH1 signaling in T-ALL. Ferrando
AA. Hematology Am Soc Hematol Educ Program. 2009:353-61.
Notch1 loss of heterozygosity causes
vascular tumors and lethal hemorrhage in mice. Liu Z, Turkoz A, Jackson EN,
Corbo JC, Engelbach JA, Garbow JR, Piwnica-Worms DR, Kopan R. J Clin Invest.
2011 Feb 1;121(2):800-8.
Characterization of Notch1 antibodies that
inhibit signaling of both normal and mutated Notch1 receptors. Aste-Amézaga M,
Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT,
Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E,
Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang H, Wang
F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE. PLoS One.
2010 Feb 8;5(2):e9094