Cell Biology

Endocytotic Notch Signal

Science Signaling  27 Jul 2010:
Vol. 3, Issue 132, pp. ec235
DOI: 10.1126/scisignal.3132ec235

The Notch receptor protein has essential roles in signaling during development in many tissues. It uses an unusual form of signaling that requires physical interactions of the signaling cell, which expresses Notch ligands on the cell surface, and the signal-receiving cell. Interaction of ligand and receptor leads to cleavage of Notch and migration of the Notch intracellular domain to the nucleus to regulate gene expression. Through a mechanism that remains the subject of speculation, endocytosis of Notch extracellular domain into the signaling cell also seems to be important for Notch signaling. Signaling after interaction of the Notch3 receptor protein with its Jagged1 ligand is enhanced by thrombospondin-2 (TSP2), an extracellular protein that interacts with numerous receptors and adhesion molecules. Meng et al. explored the function of one of these receptors—the low-density lipoprotein receptor–related protein-1 (LRP1), which regulates endocytosis. In cultured human cells, the ability of TSP2 to enhance signaling by Notch3 required expression of LRP1 by the signaling cell. In cultures with two cell types, one expressing Notch3 tagged with horseradish peroxidase and the other expressing Notch ligands, LRP1 was necessary for TSP2 to stimulate endocytosis of Notch3 by the signaling cell, although endocytosis of Notch3 still occurred in the absence of LRP1. Studies with overexpressed proteins or fragments indicated that LRP1 may directly bind both Notch3 and its ligand Jagged 1. TSP2 is also proposed to bind to Notch3 and Jagged, so the authors suggest that a multimeric complex of the four proteins could modulate the endocytotic mechanism in signaling cells that somehow functions to promote Notch signaling in the adjacent signal-receiving cell.

H. Meng, X. Zhang, S. J. Lee, D. K. Strickland, D. A. Lawrence, M. M. Wang, Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling. J. Biol. Chem. 285, 23047–23055 (2010). [Abstract] [Full Text]