Notch1 is a member of the Notch family of Type 1 single-pass transmembrane proteins that share an extracellular domain of multiple epidermal growth factor-like (EGF) repeats. Notch family members play key roles in a variety of developmental processes via the regulation of cell fate. These processes include cell-fate determination, proliferation, and cell contact-dependent signaling. In Drosophila, notch interaction with its cell-bound ligands (delta, serrate) establishes a key development intercellular signaling pathway. The Notch signaling network is an evolutionarily conserved intercellular pathway that regulates interactions between physically adjacent cells. Activation of Notch1 triggers cleavage of the cytoplasmic domain in the trans-Golgi network and releases its intracellular domain (NICD) which is then free to form the RBPJ/RBPSUH complex which in turn influences transcription of downstream target genes. Because the majority of Notch1 ligands are transmembrane proteins, it is primarily triggered via cell-to-cell contact and uses lateral inhibition mechanisms to influence local cell populations. Aberrant activation of the Notch1 pathway is associated with diseases such as bicuspid aortic valve and cancer - in particular certain leukemias. Homologues of the notch-ligands have also been identified in human, but the precise interactions between these ligands and human notch homologues is still under investigation.
Firestein’s group from Dana-Farber published Nature data dependent on usage of the Notch1 antibody to identify CDK8 as a colorectal cancer oncogene required for beta-catenin driven transformation (1). Additionally, Jundt et al employed the Notch1 antibody to examine how aberrant Notch1 expression affects the differentiation state of neoplastic B-cells in Hodgkins lymphoma (2). Their results suggest Notch1 antagonizes both E2A and early B-cell factor (EBF) transcription factors. Oncology research at the Wistar Institute used the Notch1 antibody to examine the impact of Notch1 in K-ras-induced tumorigenesis and surprisingly found that Notch1 has both oncogenic and tumor suppressor functions in pancreatic ductal adenocarcinoma (PDAC) (3). Recent experiments with the Notch1 antibody in vertebrate neurogenesis helped pinpoint the apical endfoot within both nascent neurons and intermediate neurogenic progenitors is the primary site of active Notch signaling (4). Additional experiments focused on aggressive uterine serous carcinomas (USCs) used the Notch1 antibody to better understand Notch signaling and monitor the effect of gamma-secretase on tumor growth in a specialized human xenograft model (5).
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