The cell giveth and the cell taketh away: An overview of Notch pathway activation by endocytic trafficking of ligands and receptors

Abstract

Notch signaling is firmly established as a form of cell-to-cell communication that is critical throughout development. Dysregulation of Notch has been linked to cancer and developmental disorders, making it an important target for therapeutic intervention. One aspect of this pathway that sets it apart from others is its apparent reliance on endocytosis by signal-sending and signal-receiving cells. The subtle details of endocytosis-mediated molecular processing within both ligand- and receptor-presenting cells that are required for the Notch signal to maintain fidelity remain unclear. The endosomal system has long been known to play an important role in terminating signal transduction by directing lysosomal trafficking and degradation of cell surface receptors. More recently, endocytic trafficking has also been shown to be critical for activation of signaling. This review highlights four models of endocytic processing in the context of the Notch pathway. In ligand-presenting cells, endocytosis may be required for pre-processing of ligands to make them competent for interaction with Notch receptors and/or for exerting a pulling force on the ligand/Notch complex. In receptor-presenting cells, endocytosis may be a prerequisite for Notch cleavage and thus activation and/or it could be a means of limiting ligand-independent Notch activation. Recent advances in our understanding of how and why endocytosis of Notch receptors and ligands is required for activation and termination of signaling during normal development and in disease states are discussed.

Regulation of Vascular Smooth Muscle Cell Phenotype in Three-Dimensional Coculture System by Jagged1-Selective Notch3 Signaling

“…66,67 Given that ligand internalization in the case of Jagged1-bound beads is not a likely process (note that the signal-sending cell is replaced by Jagged-1-bound beads), it is reasonable to expect that presenting Jagged1 bound to beads may not be a sufficient condition for effective Notch activation and downstream target gene expression in HCASMCs, which underscores the need for cell-cell contact in our culture system. Finally, although our study focused on the role of Jagged1 in upregulating Notch3, we are not ruling out the possibility that Notch expression may also be regulated by other signaling pathways.…”

Direct observation of proteolytic cleavage at the S2 site upon forced unfolding of the Notch negative regulatory region

“…Future work to test the influence of these preceding EGF-like repeats would, however, be of interest. A further issue to explore is whether cleavage at S1 is required for S2 cleavage, for which contradictory data exist (23,58,59), probably due to differences in organism and type of Notch receptor. Here, we show protease accessibility to S2 upon forced unfolding of hN2-NRR that possesses an intact S1 site.…”

Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis

“…Ligand-independent internalisation of the full-length Notch protein from the plasma membrane and trafficking through the degradation pathway has been suggested as a means to prevent excess Notch activation (Pratt et al, 2011). Conversely, it has been shown that the endocytosed Notch receptor can escape lysosomal degradation and becomes involved in signalling in a Dx-dependent way (Andersson et al, 2011;Baron, 2012;Guruharsha et al, 2012;Hori et al, 2004Hori et al, , 2014Hori et al, , 2012Kopan, 2012).…”