Processing of the Notch Ligand Delta by the Metalloprotease Kuzbanian

Abstract

Signaling by the Notch surface receptor controls cell fate determination in a broad spectrum of tissues. This signaling is triggered by the interaction of the Notch protein with what, so far, have been thought to be transmembrane ligands expressed on adjacent cells. Here biochemical and genetic analyses show that the ligand Delta is cleaved on the surface, releasing an extracellular fragment capable of binding to Notch and acting as an agonist of Notch activity. The ADAM disintegrin metalloprotease Kuzbanian is required for this processing event. These observations raise the possibility that Notch signaling in vivo is modulated by soluble forms of the Notch ligands.

Oscillations and patterns in spatially discrete models for developmental intercellular signalling

“…Analysis and numerical simulation demonstrates another surprising result: even with lateral inhibition in ligand production, patterns of wavelength longer than two or three cells are predicted. It has been suggested recently that lateral inhibition must be combined with other mechanisms to give longer wavelength patterns, such as cell growth [4], long-range filapodial contacts [24], or paracrine signalling [17,33]. However, we have shown that lateral inhibition can be sufficient by itself to predict longer-range patterns without the need for additional long range effects.…”

Regulation of Notch1 Signaling by Delta-like Ligand 1 Intracellular Domain through Physical Interaction

“…Delta is cleaved sequentially by the RIP mechanism probably including ADAM and gamma-secretase (Ikeuchi and Sisodia, 2003;LaVoie and Selkoe, 2003;Qi et al, 1999;Six et al, 2003), and the cleaved Dll1-IC is released from the cell membrane and translocates to the nucleus, where it suppresses notch signaling through the disruption of Notch1-IC transcriptional complex. Henceforth, the results of this study may begin to shed some light on what may be a signal cross-talk mechanism of Notch and Delta after cleavage by gamma-secretase.…”

“…It was recently demonstrated that many single transmembranespanning proteins--including Notch, Delta and amyloid precursor protein (APP)--are substrates for gamma-secretase (Koo and Kopan, 2004). Delta has also been shown to be cleaved by ADAM protease and gamma-secretase to release an intracellular domain and thereby generate Dll1-IC, which is trafficked to the nucleus (Ikeuchi and Sisodia, 2003;LaVoie and Selkoe, 2003;Qi et al, 1999;Six et al, 2003). Indeed, several groups have produced evidence of the nuclear localization of the intracellular fragments of Notch ligands.…”

Adam10 is essential for early embryonic cardiovascular development

“…ADAM10 may function as a protease to cleave both Notch and its ligands based on the results from kuz in Drosophila (Pan and Rubin, 1997;Qi et al, 1999). Furthermore, ADAM10 itself may be cleaved by other ADAMs to become a soluble and catalytically active protease (Liu et al, 2009).…”