Reversible and bidirectional signaling of notch ligands

Elenaé Vázquez-ulloa, Kai-Lan Lin, Marcela Lizano, Cecilia Sahlgren*

*Corresponding author for this work

Research output: Contribution to journalReview Article or Literature Reviewpeer-review

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The Notch signaling pathway is a direct cell-cell communication system involved in a wide variety of biological processes, and its disruption is observed in several pathologies. The pathway is comprised of a ligand-expressing (sender) cell and a receptor-expressing (receiver) cell. The canonical ligands are members of the Delta/Serrate/Lag-1 (DSL) family of proteins. Their binding to a Notch receptor in a neighboring cell induces a conformational change in the receptor, which will undergo regulated intramembrane proteolysis (RIP), liberating the Notch intracellular domain (NICD). The NICD is translocated to the nucleus and promotes gene transcription. It has been demonstrated that the ligands can also undergo RIP and nuclear translocation, suggesting a function for the ligands in the sender cell and possible bidirectionality of the Notch pathway. Although the complete mechanism of ligand processing is not entirely understood, and its dependence on Notch receptors has not been ruled out. Also, ligands have autonomous functions beyond Notch activation. Here we review the concepts of reverse and bidirectional signalization of DSL proteins and discuss the characteristics that make them more than just ligands of the Notch pathway.
Original languageEnglish
Pages (from-to)377-398
JournalCritical Reviews in Biochemistry and Molecular Biology
Issue number4
Publication statusPublished - 2022
MoE publication typeA2 Review article in a scientific journal


  • Notch pathway
  • DSL ligands
  • reversible signaling
  • bidirectional
  • Regulated Intramembrane Proteolysis (RIP)
  • ADAM
  • γ-secretase
  • PDZ


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