Journal
EMBO JOURNAL
Volume 21, Issue 3, Pages 294-302Publisher
WILEY
DOI: 10.1093/emboj/21.3.294
Keywords
extracellular cleavage; intracellular cleavage; multimerization; Notch; Notch ligand
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The biological activity, of the soluble form of the Notch ligand (sNL) and requirement of the intracellular domain (ICD) of the Notch ligand have been debated. Here we show that soluble Delta1 (sD1) activates Notch2 (N2), but much more weakly, than full-length Delta1 (fD1). Furthermore, tracing the N2 molecule after sD1 stimulation revealed that sD1 has a defect in the cleavage releasing ICD of N2 (intracellular cleavage), although it triggers cleavage in the extracellular domain of N2. This represents the molecular basis of the lower activity of sD1 and suggests the presence of an unknown mechanism regulating activation of the intracellular cleavage. The fact that Delta1 lacking its ICD (D1Delta(ICD)) exhibits the phenotype similar to that exhibited by sD1 indicates that the ICD of D1 (D1(ICD)) is involved in such an as yet unknown mechanism. Furthermore. the findings that D1Delta(ICD) acts in a dominant-negative fashion against fD1 and that the signal-transducing activity, of sD1 is enhanced by antibody-mediated cross-linking suggest that the multimerization of Delta1 mediated by, D1(ICD) may, be required for activation of the N2 intracellular cleavage.
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