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Integrity of intracellular domain of Notch ligand is indispensable for cleavage required for release of the Notch2 intracellular domain
Author(s) -
Shimizu Kiyoshi,
Chiba Shigeru,
Saito Toshiki,
Takahashi Tokiharu,
Kumano Keiki,
Hamada Yoshio,
Hirai Hisamaru
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.3.294
Subject(s) - intracellular , biology , notch signaling pathway , domain (mathematical analysis) , cleavage (geology) , microbiology and biotechnology , ligand (biochemistry) , biophysics , biochemistry , signal transduction , receptor , paleontology , fracture (geology) , mathematical analysis , mathematics
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 (D1Δ 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 D1Δ 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 multi merization of Delta1 mediated by D1 ICD may be required for activation of the N2 intracellular cleavage.