Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells.
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-Jkappa/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.
Itoh
Fumiko
F
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam.
Itoh
Susumu
S
Goumans
Marie-José
MJ
Valdimarsdottir
Gudrun
G
Iso
Tatsuya
T
Dotto
G Paolo
GP
Hamamori
Yasuo
Y
Kedes
Larry
L
Kato
Mitsuyasu
M
ten Dijke Pt
Peter
P
D000818:Animals; D052004:Bone Morphogenetic Protein Receptors; D019556:COS Cells; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D020862:GC Rich Sequence / Q000502:physiology; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051798:Inhibitor of Differentiation Protein 1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051798:Inhibitor of Differentiation Protein 1; D008565:Membrane Proteins; D009687:Nuclear Proteins; C497570:RBPJ protein, human; C497571:Rbpj protein, mouse; D017978:Receptors, Growth Factor; D051880:Receptors, Notch; D012097:Repressor Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D052004:Bone Morphogenetic Protein Receptors