Signaling by NOTCH4 (Homo sapiens)
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Description
The NOTCH4 gene locus was discovered as a frequent site of insertion for the proviral genome of the mouse mammary tumor virus (MMTV) (Gallahan and Callahan 1987). MMTV-insertion results in aberrant expression of the mouse mammary tumor gene int-3, which was subsequently discovered to represent the intracellular domain of Notch4 (Robbins et al. 1992, Uyttendaele et al. 1996).
NOTCH4 is prevalently expressed in endothelial cells (Uyttendaele et al. 1996). DLL4 and JAG1 act as ligands for NOTCH4 in human endothelial cells (Shawber et al. 2003, Shawber et al. 2007), but DLL4- and JAG1-mediated activation of NOTCH4 have not been confirmed in all cell types tested (Aste-Amezaga et al. 2010, James et al. 2014). The gamma secretase complex cleaves activated NOTCH4 receptor to release the intracellular domain fragment (NICD4) (Saxena et al. 2001, Das et al. 2004). 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 (Ramakrishnan et al. 2015) as well as proteasome-dependent degradation upon FBXW7-mediated ubiquitination (Wu et al. 2001, Tsunematsu et al. 2004).
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 (James et al. 2014).
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 (Uyttendaele et al. 2001). NOTCH4 may act to inhibit apoptosis of endothelial cells (MacKenzie et al. 2004).
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 (Raafat et al. 2009). 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 (Simoes et al. 2015). Development of int-3-induced mammary tumours in mice depends on Kit and Pdgfra signaling (Raafat et al. 2006) and on int-3-induced activaton of NFKB signaling (Raafat et al. 2017). 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 (Fukusumi et al. 2018). 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 (Qian et al. 2015).
NOTCH4 is expressed in adipocytes and may promote adipocyte differentiation (Lai et al. 2013).
During Dengue virus infection, DLL1, DLL4, NOTCH4 and HES1 are upregulated in interferon-beta (INFB) dependent manner (Li et al. 2015). NOTCH4 signaling may be affected by Epstein-Barr virus (EBV) infection, as the EBV protein BARF0 binds to NOTCH4 (Kusano and Raab-Traub 2001). View original pathway at:Reactome.
NOTCH4 is prevalently expressed in endothelial cells (Uyttendaele et al. 1996). DLL4 and JAG1 act as ligands for NOTCH4 in human endothelial cells (Shawber et al. 2003, Shawber et al. 2007), but DLL4- and JAG1-mediated activation of NOTCH4 have not been confirmed in all cell types tested (Aste-Amezaga et al. 2010, James et al. 2014). The gamma secretase complex cleaves activated NOTCH4 receptor to release the intracellular domain fragment (NICD4) (Saxena et al. 2001, Das et al. 2004). 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 (Ramakrishnan et al. 2015) as well as proteasome-dependent degradation upon FBXW7-mediated ubiquitination (Wu et al. 2001, Tsunematsu et al. 2004).
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 (James et al. 2014).
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 (Uyttendaele et al. 2001). NOTCH4 may act to inhibit apoptosis of endothelial cells (MacKenzie et al. 2004).
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 (Raafat et al. 2009). 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 (Simoes et al. 2015). Development of int-3-induced mammary tumours in mice depends on Kit and Pdgfra signaling (Raafat et al. 2006) and on int-3-induced activaton of NFKB signaling (Raafat et al. 2017). 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 (Fukusumi et al. 2018). 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 (Qian et al. 2015).
NOTCH4 is expressed in adipocytes and may promote adipocyte differentiation (Lai et al. 2013).
During Dengue virus infection, DLL1, DLL4, NOTCH4 and HES1 are upregulated in interferon-beta (INFB) dependent manner (Li et al. 2015). NOTCH4 signaling may be affected by Epstein-Barr virus (EBV) infection, as the EBV protein BARF0 binds to NOTCH4 (Kusano and Raab-Traub 2001). View original pathway at:Reactome.
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Besides NICD4, RBPJ and MAML, NOTCH4 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex. Since disruption of the RBPJ:NCOR corepressor and MAML-mediated recruitment of transcriptional activators has not been studied in the context of NICD4, it is not shown here. More details are available in the pathway Signaling by NOTCH1.
NOTCH4 does not alter DNA binding specificity of RBPJ (Del Bianco et al. 2010).