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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, [https://en.wikipedia.org/wiki/Furin Furin]-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the <scene name='86/868190/Hd/1'>heterodimerization (HD) domain</scene>. 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_domaintrue/5'>Site 2</scene>, present within the <scene name='86/868190/Nrr_domain_alonecentre/2'>negative regulatory region (NRR) domain</scene>, is thus exposed for cleavage by a [https://en.wikipedia.org/wiki/ADAM_(protein) disintegrin and metalloprotease (ADAM)]. Notch cleavage at <scene name='86/868190/S2_domaintrue/5'>S2</scene> generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the [https://en.wikipedia.org/wiki/Gamma_secretase 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 [https://www.uniprot.org/uniprot/Q06330 RPBJ] 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>
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, [https://en.wikipedia.org/wiki/Furin Furin]-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the <scene name='86/868190/Hd/1'>heterodimerization (HD) domain</scene>. 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_domaintrue/5'>Site 2</scene>, present within the <scene name='86/868190/Nrr_domain_alonecentre/2'>negative regulatory region (NRR) domain</scene>, is thus exposed for cleavage by a [https://en.wikipedia.org/wiki/ADAM_(protein) disintegrin and metalloprotease (ADAM)]. Notch cleavage at <scene name='86/868190/S2_domaintrue/5'>S2</scene> generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the [https://en.wikipedia.org/wiki/Gamma_secretase 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 [https://www.uniprot.org/uniprot/Q06330 RPBJ] 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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<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, therefore relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> are leading to an increase of Notch signalling, generating an increase in the expression of the target gene, finally causing unbalance in the levels of Notch ICD in the cell. 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 T-cell acute lymphoblastic leukemia (T-ALL)<ref> PMID: 15472075 </ref>. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of [https://en.wikipedia.org/wiki/Ovarian_cancer 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" />
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<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, therefore relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> are leading to an increase of Notch signalling, generating an increase in the expression of the target gene, finally causing unbalance in the levels of Notch ICD in the cell. 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 T-cell acute lymphoblastic leukemia (T-ALL)<ref> PMID: 15472075 </ref>. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian adenocarcinomas]. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers and [https://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lung lung adenocarcinoma]. <ref name="oncogene" />
Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on NOTCH3-selective inhibitory antibodies <ref> PMID: 27157619</ref>.<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref>
Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on NOTCH3-selective inhibitory antibodies <ref> PMID: 27157619</ref>.<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref>

Current revision

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Crystal structure of Notch3 NRR

Drag the structure with the mouse to rotate

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 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
  2. ↑ 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
  3. ↑ Tumer E, Broer A, Balkrishna S, Julich T, Broer S. Enterocyte-specific regulation of the apical nutrient transporter SLC6A19 (B(0)AT1) by transcriptional and epigenetic networks. J Biol Chem. 2013 Nov 22;288(47):33813-33823. doi: 10.1074/jbc.M113.482760. Epub , 2013 Oct 11. PMID:24121511 doi:http://dx.doi.org/10.1074/jbc.M113.482760
  4. ↑ 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
  5. ↑ 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
  6. ↑ Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004 Oct 8;306(5694):269-71. doi: 10.1126/science.1102160. PMID:15472075 doi:http://dx.doi.org/10.1126/science.1102160
  7. ↑ Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, Capodieci P, Deplazes-Lauber J, Petropoulos K, Thiel P, Ponsel D, Hee Choi S, LeMotte P, London A, Goetcshkes M, Nolin E, Jones MD, Slocum K, Kluk MJ, Weinstock DM, Christodoulou A, Weinberg O, Jaehrling J, Ettenberg SA, Buckler A, Blacklow SC, Aster JC, Fryer CJ. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene. 2016 May 9. doi: 10.1038/onc.2016.133. PMID:27157619 doi:http://dx.doi.org/10.1038/onc.2016.133
  8. ↑ 8.0 8.1 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
  9. ↑ Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012 Jun;23(4):450-7. doi: 10.1016/j.semcdb.2012.01.010., Epub 2012 Jan 28. PMID:22306179 doi:http://dx.doi.org/10.1016/j.semcdb.2012.01.010
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