TY - JOUR

T1 - Control of endothelial cell tube formation by Notch ligand intracellular domain interactions with activator protein 1 (AP-1)

AU - Forghany, Zary

AU - Robertson, Francesca

AU - Lundby, Alicia

AU - Olsen, Jesper V.

AU - Baker, David A

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Journal Article

KW - Notch pathway

KW - signaling

KW - AP1 transcription factor (AP-1)

KW - gene regulation

KW - angiogenesis

U2 - 10.1074/jbc.M117.819045

DO - 10.1074/jbc.M117.819045

M3 - Journal article

C2 - 29196606

VL - 293

SP - 1229

EP - 1242

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 4

ER -