Signaling by NOTCH4

NOTCH4 is prevalently expressed in endothelial cells. DLL4 and JAG1 act as ligands for NOTCH4 in human endothelial cells, but DLL4- and JAG1-mediated activation of NOTCH4 have not been confirmed in all cell types tested. The gamma secretase complex cleaves activated NOTCH4 receptor to release the intracellular domain fragment (NICD4). NICD4 traffics to the nucleus where it acts as a transcription factor and stimulates expression of NOTCH target genes HES1, HES5, HEY1 and HEY2, as well as VEGFR3 and ACTA2 (Lin et al. 2002, Raafat et al.2004, Tsunematsu et al. 2004, Shawber et al. 2007, Tang et al. 2008, Bargo et al. 2010). NOTCH4 signaling can be downregulated by AKT1 phosphorylation-induced cytoplasmic retention as well as proteasome-dependent degradation upon FBXW7-mediated ubiquitination.

NOTCH4 was reported to inhibit NOTCH1 signaling in-cis, by binding to NOTCH1 and interfering with the S1 cleavage of NOTCH1, thus preventing production of functional NOTCH1 heterodimers at the cell surface.

NOTCH4 is involved in development of the vascular system. Overexpression of constitutively active Notch4 in mouse embryonic vasculature results in abnormal vessel structure and patterning. NOTCH4 may act to inhibit apoptosis of endothelial cells.

Expression of int-3 interferes with normal mammary gland development in mice and promotes tumorigenesis. The phenotype of mice expressing int-3 in mammary glands is dependent on the presence of Rbpj. JAG1 and NOTCH4 are upregulated in human ER+ breast cancers resistant to anti-estrogen therapy, which correlates with elevated expression of NOTCH target genes HES1, HEY1 and HEY2, and is associated with increased population of breast cancer stem cells and distant metastases. Development of int-3-induced mammary tumours in mice depends on Kit and Pdgfra signaling and on int-3-induced activaton of NFKB signaling. In head and neck squamous cell carcinoma (HNSCC), high NOTCH4 expression correlates with elevated HEY1 levels, increased cell proliferation and survival, epithelial-to-mesenchymal transition (EMT) phenotype and cisplatin resistance. In melanoma, however, exogenous NOTCH4 expression correlates with mesenchymal-to-epithelial-like transition and reduced invasiveness (Bonyadi Rad et al. 2016). NOTCH4 is frequently overexpressed in gastric cancer. Increased NOTCH4 levels correlate with activation of WNT signaling and gastric cancer progression.

NOTCH4 is expressed in adipocytes and may promote adipocyte differentiation.

During Dengue virus infection, DLL1, DLL4, NOTCH4 and HES1 are upregulated in interferon-beta (INFB) dependent manner. NOTCH4 signaling may be affected by Epstein-Barr virus (EBV) infection, as the EBV protein BARF0 binds to NOTCH4.