An updated evolutionary study of the Notch family reveals a new ancient origin and novel invariable motifs as potential pharmacological targets

Dimitrios Vlachakis; Louis Papageorgiou; Ariadne Papadaki; Maria Georga; Sofia Kossida; Elias Eliopoulos

doi:10.7717/peerj.10334

An updated evolutionary study of the Notch family reveals a new ancient origin and novel invariable motifs as potential pharmacological targets

PeerJ. 2020 Nov 5:8:e10334. doi: 10.7717/peerj.10334. eCollection 2020.

Authors

Dimitrios Vlachakis^{1

2

3}, Louis Papageorgiou⁴, Ariadne Papadaki¹, Maria Georga¹, Sofia Kossida⁵, Elias Eliopoulos¹

Affiliations

¹ Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece.
² University Research Institute of Maternal and Child Health & Precision Medicine, and UNESCO Chair on Adolescent Health Care, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.
³ Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
⁴ Department of Informatics and Telecommunications, National and Kapodistrian University of Athens, Athens, Greece.
⁵ IMGT, The International ImMunoGeneTics Information System, Université de Montpellier, Laboratoire d'ImmunoGénétique Moléculaire and Institut de Génétique Humaine, University of Montpellier, Montpellier, France.

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.

Keywords: Developmental processes; Evolutionary analysis; Notch family; Notch signaling pathway; Pharmacological target.

Grants and funding

Dimitrios Vlachakis received funding from: (i) Microsoft Azure for Genomics Research Grant (CRM:0740983); (ii) Amazon Web Services Cloud for Genomics Research Grant (309211522729); (iii) AdjustEBOVGP-Dx (RIA2018EF-2081): Biochemical Adjustments of native EBOV Glycoprotein in Patient Sample to Unmask target Epitopes for Rapid Diagnostic Testing. A European and Developing Countries Clinical Trials Partnership (EDCTP2) under the Horizon 2020 “Research and Innovation Actions” DESCA. Elias Eliopoulos received funding by the project “INSPIRED-The National Research Infrastructures on Integrated Structural Biology, Drug Screening Efforts and Drug Target Functional Characterization” (Grant MIS 5002550) and by the project: “OPENSCREEN-GR An Open-Access Research Infrastructure of Chemical Biology and Target-Based Screening Technologies for Human and Animal Health, Agriculture and the Environment” (Grant MIS 5002691), which are implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.