Notch signaling pathway

Notch is a cell-cell signaling pathway that is involved in a host of activities including development, oncogenesis, skeletal homeostasis, and much more. More specifically, research has demonstrated the importance of Notch signaling in osteogenic differentiation, bone healing, and the development of the skeleton. The craniofacial skeleton is complex and understanding its development has remained an important focus in biology. In a review, we briefly summarize what recent research has revealed about Notch signaling and the current understanding of how the skeleton, skull, and face develop. They then discuss the crucial role that Notch plays in both craniofacial development and the skeletal system, and what importance it may play in the future 1).

Oncolytic herpes simplex virus type 1 (oHSV) infection of brain tumors activates NOTCH. NOTCH induced immunosuppressive myeloid cell recruitment limited anti-tumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy 2)

The NOTCH signaling pathway, regulates stem cells during normal development and stemlike cells in cancer.

It is a highly conserved cell signaling system present in most multicellular organisms, and is altered in many cancers.

Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with 4 receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes.

Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

Notch signaling promotes proliferative signaling during neurogenesis, and its activity is inhibited by Numb to promote neural differentiation.

It is suggested to promote the development and maintenance of cerebral arteriovenous malformations (AVMs), and an increasing wall shear stress (WSS) contributes to AVM rupture. Little is known about whether WSS impacts Notch signaling, which is important for understanding the angiogenesis of AVMs. WSS was measured in arteriovenous fistulas (AVF) surgically created in 96 rats at different time points over a period of 84 days. The expression of Notch receptors 1 and 4 and their ligands, Delta1 and 4, Jagged1, and Notch downstream gene target Hes1 was quantified in “nidus” vessels. The interaction events between Notch receptors and their ligands were quantified using proximity ligation assay. There was a positive correlation between WSS and time (r = 0.97; P < 0.001). The expression of Notch receptors and their ligands was upregulated following AVF formation. There was a positive correlation between time and the number of interactions between Notch receptors and their ligands aftre AVF formation (r = 0.62, P < 0.05) and a positive correlation between WSS and the number of interactions between Notch receptors and their ligands (r = 0.87, P < 0.005). In conclusion, an increasing WSS may contribute to the angiogenesis of AVMs by activation of Notch signaling 3).

Pakvasa M, Haravu P, Boachie-Mensah M, Jones A, Coalson E, Liao J, Zeng Z, Wu D, Qin K, Wu X, Luo H, Zhang J, Zhang M, He F, Mao Y, Zhang Y, Niu C, Wu M, Zhao X, Wang H, Huang L, Shi D, Liu Q, Ni N, Fu K, Lee MJ, Wolf JM, Athiviraham A, Ho SS, He TC, Hynes K, Strelzow J, El Dafrawy M, Reid RR. Notch signaling: Its essential roles in bone and craniofacial development. Genes Dis. 2020 Apr 11;8(1):8-24. doi: 10.1016/j.gendis.2020.04.006. PMID: 33569510; PMCID: PMC7859553.
Otani Y, Yoo JY, Lewis CT, Chao S, Swanner J, Shimizu T, Kang JM, Murphy SA, Rivera-Caraballo K, Hong B, Glorioso JC, Nakashima H, Lawler SE, Banasavadi-Siddegowda Y, Heiss JD, Yan Y, Pei G, Caliguri MA, Zhao Z, Chiocca EA, Yu J, Kaur B. NOTCH induced MDSC recruitment after oHSV virotherapy in CNS cancer models modulates anti-tumor immunotherapy. Clin Cancer Res. 2022 Jan 12:clincanres.2347.2021. doi: 10.1158/1078-0432.CCR-21-2347. Epub ahead of print. PMID: 35022322.
Tu J, Li Y, Hu Z. Notch1 and 4 signaling responds to an increasing vascular wall shear stress in a rat model of arteriovenous malformations. Biomed Res Int. 2014;2014:368082. doi: 10.1155/2014/368082. Epub 2014 Jan 20. PubMed PMID: 24563863.
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