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It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors play an important role in cancer development in mammals. These oncogenic mechanisms of the ''Notch'' receptors are dependant on its intracelluclar signaling. Therefore, in order to understand how the cancer develops due to these receptors, it is necessary to understand the [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch pathway].
It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors play an important role in cancer development in mammals. These oncogenic mechanisms of the ''Notch'' receptors are dependant on its intracelluclar signaling. Therefore, in order to understand how the cancer develops due to these receptors, it is necessary to understand the [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch pathway].
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As an example, the target genes in the pathway of [https://en.wikipedia.org/wiki/Notch_3 NOTCH3] or other subtypes of the ''Notch'' receptors are expressed by a variety of translocation, [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] and activation of ligands associated to it. Following translation, Furin-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the heterodimerization (HD) domain. The ''Notch'' receptor on the signal‐receiving cell binds to a ligand on the cell surface of a neighboring signal‐sending cell, causing it to get activated. This binding causes a change in the conformation of the receptor. Site 2 (S2), present within the negative regulatory region (NRR) domain, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at S2 generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the γ‐secretase complex. Thus, the ''Notch'' receptor is cleaved by the γ-secretase complex. Following γ-secretase cleavage, the intracellular domain (ICD) of NOTCH3 translocates to the nucleus where it interacts with the DNA-binding factor RBPJ and co-activators of the [https://en.wikipedia.org/wiki/MAML1 mastermind-like (MAML)] family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref>
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As an example, the target genes in the pathway of [https://en.wikipedia.org/wiki/Notch_3 NOTCH3] or other subtypes of the ''Notch'' receptors are expressed by a variety of translocation, [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] and activation of ligands associated to it. Following translation, Furin-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the heterodimerization (HD) domain. The ''Notch'' receptor on the signal‐receiving cell binds to a ligand on the cell surface of a neighboring signal‐sending cell, causing it to get activated. This binding causes a change in the conformation of the receptor. <scene name='86/868190/S2_domain/1'>Site 2 (S2)</scene>, present within the negative regulatory region (NRR) domain, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at S2 generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the γ‐secretase complex. Thus, the ''Notch'' receptor is cleaved by the γ-secretase complex. Following γ-secretase cleavage, the intracellular domain (ICD) of NOTCH3 translocates to the nucleus where it interacts with the DNA-binding factor RBPJ and co-activators of the [https://en.wikipedia.org/wiki/MAML1 mastermind-like (MAML)] family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref>
NRR mutations act by destabilizing or completely unfolding the HD domain, relaxing the interface that protects the S2 site. These mutations associated with the HD domain in the NRR domain lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of [https://science.sciencemag.org/content/306/5694/269 T-cell acute lymphoblastic leukemia (T-ALL)]. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" />
NRR mutations act by destabilizing or completely unfolding the HD domain, relaxing the interface that protects the S2 site. These mutations associated with the HD domain in the NRR domain lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of [https://science.sciencemag.org/content/306/5694/269 T-cell acute lymphoblastic leukemia (T-ALL)]. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" />

Revision as of 21:42, 14 January 2021

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Crystal structure of Notch3 NRR in complex with 20358 Fab

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References

  1. ↑ Guo Z, Ohlstein B. Stem cell regulation. Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science. 2015 Nov 20;350(6263). pii: 350/6263/aab0988. doi:, 10.1126/science.aab0988. PMID:26586765 doi:http://dx.doi.org/10.1126/science.aab0988
  2. ↑ Callahan R, Smith GH. MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene. 2000 Feb 21;19(8):992-1001. doi: 10.1038/sj.onc.1203276. PMID:10713682 doi:http://dx.doi.org/10.1038/sj.onc.1203276
  3. ↑ Aburjania Z, Jang S, Whitt J, Jaskula-Stzul R, Chen H, Rose JB. The Role of Notch3 in Cancer. Oncologist. 2018 Aug;23(8):900-911. doi: 10.1634/theoncologist.2017-0677. Epub, 2018 Apr 5. PMID:29622701 doi:http://dx.doi.org/10.1634/theoncologist.2017-0677
  4. ↑ 4.0 4.1 4.2 Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133
  5. ↑ 5.0 5.1 Aster JC, Pear WS, Blacklow SC. The Varied Roles of Notch in Cancer. Annu Rev Pathol. 2017 Jan 24;12:245-275. doi:, 10.1146/annurev-pathol-052016-100127. Epub 2016 Dec 5. PMID:27959635 doi:http://dx.doi.org/10.1146/annurev-pathol-052016-100127
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