Notch signaling pathway: architecture, disease, and therapeutics

Abstract

The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

“…NOTCH family proteins function as receptors for membrane-bound ligands Jagged-1, Jagged-2, and Delta-1 to regulate cell fate and development through the formation of transcriptional regulator complexes [ 24 , 25 ]. Aberrant NOTCH expression has been linked to the progression of various types of cancer [ 66 ].…”

Notch Signaling in Breast Tumor Microenvironment as Mediator of Drug Resistance

“…Different Notch receptors (Notch1 to Notch4) ( Figure 1 A) and canonical activators of the core Notch pathway, the Delta/Serrate/Lag-2 (DSL) ligands Jagged (JAG) 1 and 2, and Delta-like ligand 1 (Dll1), 3 (Dll3) and 4 (Dll4) have been defined; moreover, non-canonical Notch ligands Delta-like 1 and 2 homolog (DLK 1 and 2) are known ( Figure 1 B) [ 16 , 17 ].…”

“…Notch receptors are composed of N-terminal EGF repeats, located at the extracellular portion of Notch receptor transmembrane proteins [ 16 ]; a negative regulatory region (NRR) at a juxtamembrane portion; a transcriptional activation domain with high binding affinity for RBPJ; six Ankyrin (ANK) repeats, with low binding affinity for RBPJ and high affinity for Deltex (DTX); and a C-terminal degron domain rich in the amino acids Proline, Glutamate, Serine, and Threonine (PEST) at the intracellular region [ 16 ]. After the interaction of specific ligands, the first proteolytic cleavage of the Notch protein is followed by a further subsequent proteolytic cleavage mediated by the γ-secretase enzyme complex [ 17 ]. Therefore, the released receptor portion, the so-called Notch Intracellular Domain (NICD), moves into the nucleus where it forms a complex with the DNA binding protein RBPJ, which recruits another co-activator, a member of the MAML family [ 17 ].…”

Mechanisms during Osteogenic Differentiation in Human Dental Follicle Cells

“…In addition, the NOTCH signaling pathway also regulates the osteogenic differentiation of DFCs [ 56 ]. The family of NOTCH proteins are transmembrane receptors that mediate communication between neighboring cells and are involved in a number of developmental processes [ 57 ]. The binding of the NOTCH ligand triggers the cleavage of an intracellular domain of NOTCH (NICD) translocates into the nucleus and affects the transcription like a transcription factor.…”