Abstract
Notch family proteins play a key role in a variety of developmental processes by controlling cell fate decisions and operating in a great number of biological processes in several organ systems, such as hematopoiesis, somatogenesis, vasculogenesis, neurogenesis and homeostasis. The Notch signaling pathway is crucial for the majority of developmental programs and regulates multiple pathogenic processes. Notch family receptors’ activation has been largely related to its multiple effects in sustaining oncogenesis. The Notch signaling pathway constitutes an ancient and conserved mechanism for cell to cell communication. Much of what is known about Notch family proteins function comes from studies done in Caenorhabditis Elegans and Drosophila Melanogaster. Although, human Notch homologs had also been identified, the molecular mechanisms which modulate the Notch signaling pathway remained substantially unknown. In this study, an updated evolutionary analysis of the Notch family members among 603 different organisms of all kingdoms, from bacteria to humans, was performed in order to discover key regions that have been conserved throughout evolution and play a major role in the Notch signaling pathway. The major goal of this study is the presentation of a novel updated phylogenetic tree for the Notch family as a reliable phylogeny “map”, in order to correlate information of the closely related members and identify new possible pharmacological targets that can be used in pathogenic cases, including cancer.
Highlights
The Notch gene was originally discovered by Dexter (1914) and it was named from the irregular notched wing phenotype of Drosophila melanogaster, caused by the loss-offunction in the responsible gene’s after a point mutation
The length of the Notch family proteins ranges between ≈71 aa and ≈4,835 aa
Notch family evolution In this study, we identified novel Notch protein clusters from various kingdoms extending from bacteria to chordates and conducted a comprehensive phylogenetic analysis in order to confirm and expand the evolutionary history of the Notch family (Fig. 8)
Summary
The Notch gene was originally discovered by Dexter (1914) and it was named from the irregular notched wing phenotype of Drosophila melanogaster, caused by the loss-offunction in the responsible gene’s after a point mutation. Notch protein and its homologs, Notch, Notch, Notch, Notch, LIN-12 and GPL-1 have been identified in genomes from all kingdoms, indicating the progressive differentiation of Notch family. Their length varies from ≈110 amino acids in bacteria (Durieux et al, 2019) to ≈4,500 amino acids (aa) in animals (Fairclough et al, 2013). Notch family members are evolutionary conserved, type-1 transmembrane glycoproteins, that function both as transmembrane receptors for ligands and transcription factors (Kopan & Ilagan, 2009). They regulate cell fate determination and promote cell differentiation, maintenance and survival. These proteins have either overlapping or unique cellular functions, but these functions remain quite unclarified, in the majority of the organisms found (Hogan & Bautch, 2004)
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