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Notch pathway plays a key role in several processes, including
stem-cell self-renewal, proliferation, and cell differentiation.
Several studies identified recurrent mutations in hematological
malignancies making Notch one of the most desirable targets in leukemia
and lymphoma. The Notch signaling mediates resistance to therapy and
controls cancer stem cells supporting the development of on-target
therapeutic strategies to improve patients’ outcome. In this brief
review, we outline the therapeutic potential of targeting Notch pathway
in T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia,
and mantle cell lymphoma..
1. A) The
schema shows domain organization of NOTCH protein (NOTCH1 shown). The
extracellular domain of NOTCH receptor consists of multiple EGF repeats
followed by the NRR (negative regulatory region), which consists of
three LNR (Lin-12 and Notch repeats) domains and HD (heterodimerization
domain). The intracellular domain of NOTCH receptor consists of a
membrane proximal RAM (RBPJ associated molecule) domain, ANK (ankyrin
repeats), and a C- terminal TAD (trans-activation domain) comprised of
three NLS (nuclear localization sequences) and degron-containing PEST
(rich in proline, glutamate, serine, and threonine) sequence.
B) An overview of Notch1 signaling and proteolytic processing in the presence of SERCA inhibition. NOTCH1 receptor is a cell surface protein. In physiological condition interaction with the Notch ligand, such as JAG1-2 or Dll-4, initiates proteolytic cleavage at the extracellular site by a metalloprotease (TACE) followed by a γ-secretase (GSI) cleavage, resulting in the release of ICN1. ICN1 is then translocated into the nucleus where it interacts with CSL and recruits coactivators to form a transcription-activating complex. In the presence of NOTCH1 mutations, ICN1 is constitutively active and avoids activation through ligand interaction. Inhibition of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) leads to alteration in NOTCH1 trafficking causing a loss of NOTCH1 proteins on the surface of the cells and an accumulation of full-length polypeptides on the endoplasmic reticulum/Golgi region. The consequent lack of TACE and GSI substrate causes a reduction in ICN1 level.
|Figure 2. The figure shows an overview of therapeutic targeting of Notch signaling.|
Targeting Extracellular NOTCH1
Targeting the γ-Secretase Complex
Targeting NOTCH Trafficking
Targeting NOTCH Degradation
Targeting ICN1 Complex