Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells

Abstract

Notch and bone morphogenetic protein signaling pathways are important for cellular differentiation, and both have been implicated in vascular development. In many cases the two pathways act similarly, but antagonistic effects have also been reported. The underlying mechanisms and whether this is caused by an interplay between Notch and BMP signaling is unknown. Here we report that expression of the Notch target gene, Herp2, is synergistically induced upon activation of Notch and BMP receptor signaling pathways in endothelial cells. The synergy is mediated via RBP‐Jκ/CBF‐1 and GC‐rich palindromic sites in the Herp2 promoter, as well as via interactions between the Notch intracellular domain and Smad that are stabilized by p/CAF. Activated Notch and its downstream effector Herp2 were found to inhibit endothelial cell (EC) migration. In contrast, BMP via upregulation of Id1 expression has been reported to promote EC migration. Interestingly, Herp2 was found to antagonize BMP receptor/Id1‐induced migration by inhibiting Id1 expression. Our results support the notion that Herp2 functions as a critical switch downstream of Notch and BMP receptor signaling pathways in ECs.

Coordinated Activation of Notch, Wnt, and Transforming Growth Factor-β Signaling Pathways in Bone Morphogenic Protein 2-induced Osteogenesis

“…Expression of constitutively active Notch inhibits differentiation of neural and myogenic cells and promotes generation of hematopoietic stem cells (60 -62). Very recent studies have shown that BMP and Notch signaling do collaborate during differentiation of myogenic and endothelial cells and that Hey1 is a crucial player in this collaboration (63,64). Our data in osteoblast cells show that even transient inhibition of Hey1 expression leads to enhanced matrix mineralization, a sign of their maturation, by osteoblast.…”

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

“…It is well established that Hes1 expression can be regulated by Notch/Rbpjκ-independent signaling before E8.5 (Hatakeyama et al, 2004;Kageyama et al, 2005). Additionally, Rbpjκ-independent expression of Notch factors, including Hes genes, can be mediated by members of the BMP (Dahlqvist et al, 2003;Itoh et al, 2004) Kadesch, 2001), WNT/β-catenin (Axelrod et al, 1996;Hayward et al, 2005) and Shh (Wall et al, 2009) pathways throughout embryonic development. However, only a few studies have shown that Hes5 can be modulated by Notch/Rbpjκ-independent signaling occurring at two distinct time points: before E8.5 (Donoviel et al, 1999;Hitoshi et al, 2011) and during adult neurogenesis (Matsuda et al, 2012).…”

Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-β signaling

“…TGF-b or BMP induces the expression of several genes that are also known target genes for Notch1, such as Hes-1 (Blokzijl et al, 2003), Hey1 (Zavadil et al, 2004), Hes-5 (Takizawa et al, 2003), Herp2 (Itoh et al, 2004) and the Notch ligand Jagged1 (Zavadil et al, 2004). However, information as to whether Notch1 or Notch4 can modify the TGF-b signaling pathway and the response of cells to TGF-b is limited.…”

“…In Blokzijl's study (2003) (Takizawa et al, 2003) and Herp2 (Itoh et al, 2004). Takizawa et al (2003) showed that BMP2 enhances the expression of Hes5 in mouse neuroepithelial cells.…”

“…However, Smad1 was found to only weakly interact with ICD1. Itoh et al (2004) reported that the ICD1 target gene Herp2 is synergistically induced by BMP6 and ICD1. The Herp2 promoter has two CSL-binding elements and multiple GC-rich palindromic sites that contain BMP co-SBE sites (Korchynskyi and ten Dijke, 2002).…”