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Abstract
Notch signaling is a ubiquitous signal transduction pathway found in most if not all metazoan cell types characterized to date. It is indispensable for cell differentiation as well as tissue growth, tissue remodeling, and apoptosis. Although the canonical Notch signaling pathway is well characterized, accumulating evidence points to the existence of multiple, less well-defined layers of regulation. In this study, we investigated the function of the intracellular domain (ICD) of the Notch ligand Delta-like 4 (DLL4). We provide evidence that the DLL4 ICD is required for normal DLL4 subcellular localization. We further show that it is cleaved and interacts with the JUN proto-oncogene, which forms part of the activator protein 1 (AP-1) transcription factor complex. Mechanistically, the DLL4 ICD inhibited JUN binding to DNA and thereby controlled the expression of JUN target genes, including DLL4 Our work further demonstrated that JUN strongly stimulates endothelial cell tube formation and that DLL4 constrains this process. These results raise the possibility that Notch/DLL4 signaling is bidirectional and suggest that the DLL4 ICD could represent a point of cross-talk between Notch and receptor tyrosine kinase (RTK) signaling.
Highlights
Notch signaling is a ubiquitous signal transduction pathway found in most if not all metazoan cell types characterized to date
We provide evidence that the Delta-like 4 (DLL4) intracellular domain (ICD) is required for normal DLL4 subcellular localization
These results raise the possibility that Notch/DLL4 signaling is bidirectional and suggest that the DLL4 ICD could represent a point of cross-talk between Notch and receptor tyrosine kinase (RTK) signaling
Summary
The amino acid sequence of the intracellular domain of DLL4 (hereafter referred to as DLL4INTRA) has been highly conserved throughout vertebrate evolution (Fig. 1A). It is possible that DLL4 monomers oligomerize/dimerize, which could render the C terminus inaccessible for JUN interactions.5 These data highlight potentially a dual role for the DLL4ICD: it can interact with the bZIP domain of JUN, and in addition it encodes a PDZ-binding domain that mediates a functional interaction with MUPP1. DLL4INTRA, but not DLL4N, inhibited JUN association to the AP-1 site (Fig. 3B) and could impede AP-1 dimerization (Fig. 3B) Both the PDZ-binding motif of DLL4INTRA and sequences N-terminal of the LEVD motif were dispensable for this inhibition (Fig. 3C), whereas the highly conserved C-terminal 20 amino acids of DLL4 appear to be necessary for inhibiting in vitro JUN DNA binding (in agreement with our observation that these sequences are needed for binding to the JUN bZIP domain; see Fig.2F).JUNrepressesoractivatesgeneexpressioninacontext-dependent fashion by docking on target promoters and through the differential recruitment of corepressors and coactivators. To test whether these effects could have resulted from DLL4INTRA directly occluding JUN DNA binding, we investigated JUN recruitment to the proximal pro-
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