Sandbox Reserved 1657: Difference between revisions
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== Disease == | == Disease == | ||
It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors | It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors plays an important role in cancer development in mammals and changes the activity of these receptors which dysfunction can be associated with various benign and malignant diseases such as [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142501/ T-ALL (T-lineage acute lymphoblastic leukemia)]. T-ALL is characterized by the uncontrolled proliferation of T-cell [https://en.wikipedia.org/wiki/Lymphoblast lymphoblasts] in the blood, the brown marrow and the tissues. 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]. | ||
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 <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 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 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> | 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 <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 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 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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== Relevance == | == Relevance == | ||
The ''Notch'' | The ''Notch'' signalling pathway regulates cell-to-cell interaction, [https://en.wikipedia.org/wiki/Embryonic_development embryogenesis] as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lies in the mutations of the ''Notch'' gene that have been identified as a contributing factor to an extensive range of cancers in mammals. These mutations can change the activity of the pathway rendering it capable of causing [https://pubmed.ncbi.nlm.nih.gov/22306179/ various diseases] depending on the sub-type of the targeted ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role.<ref name="roles" /> | ||
The ''Notch'' | The ''Notch'' signalling pathway has been studied comprehensively and various aspects of this pathway are very well known. Despite this, it is essential to study the pathway further, so as to understand the role it plays in cancer development and explore novel treatment strategies focusing on the ''Notch'' pathway. | ||
