TY - JOUR
T1 - Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1
AU - Liu, Zhao Jun
AU - Xiao, Min
AU - Balint, Klara
AU - Soma, Akinobu
AU - Pinnix, Chelsea C.
AU - Capobianco, Anthony J.
AU - Velazquez, Omaida C.
AU - Herlyn, Meenhard
PY - 2006/5
Y1 - 2006/5
N2 - The requirement for Notch signaling in vasculogenesis and angiogenesis is well documented. In a previous study, we showed that activation of the Notch pathway in endothelial cells induces differentiation-associated growth arrest; however, the underlying mechanism remains to be elucidated. Here, we show that activation of the Notch pathway by either stimulation of cell surface Notch receptors with crosslinked soluble Delta-like 4 (sDll4)/Jagged1 (sJag1) or constitutive expression of the Notch1 intracellular domain (NIC) suppresses endothelial cell proliferation. This suppression is mediated by the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Following Notch1 activation, both pathways were suppressed in endothelial cells, and alterations in MAPK or PI3K/Akt pathway activity reversed Notch1-induced growth inhibition. Furthermore, we found the effect of Notch1 on endothelial cells to require Mastermind-like (MAML). Overexpression of a dominant-negative mutant of MAML1 antagonized the effects of activated Notch1 on the MAPK and PI3K/Akt pathways. Ectopic expression of Hairy/Enhancer of Split 1 (HES1) consistently reproduced the inhibitory effect of NIC on endothelial cell proliferation. Together, our data demonstrate that the Notch/MAML-HES signaling cascade can regulate both MAPK and PI3K/Akt pathways, which suggests a molecular mechanism for the inhibitory effect of Notch signaling on endothelial cell proliferation.
AB - The requirement for Notch signaling in vasculogenesis and angiogenesis is well documented. In a previous study, we showed that activation of the Notch pathway in endothelial cells induces differentiation-associated growth arrest; however, the underlying mechanism remains to be elucidated. Here, we show that activation of the Notch pathway by either stimulation of cell surface Notch receptors with crosslinked soluble Delta-like 4 (sDll4)/Jagged1 (sJag1) or constitutive expression of the Notch1 intracellular domain (NIC) suppresses endothelial cell proliferation. This suppression is mediated by the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Following Notch1 activation, both pathways were suppressed in endothelial cells, and alterations in MAPK or PI3K/Akt pathway activity reversed Notch1-induced growth inhibition. Furthermore, we found the effect of Notch1 on endothelial cells to require Mastermind-like (MAML). Overexpression of a dominant-negative mutant of MAML1 antagonized the effects of activated Notch1 on the MAPK and PI3K/Akt pathways. Ectopic expression of Hairy/Enhancer of Split 1 (HES1) consistently reproduced the inhibitory effect of NIC on endothelial cell proliferation. Together, our data demonstrate that the Notch/MAML-HES signaling cascade can regulate both MAPK and PI3K/Akt pathways, which suggests a molecular mechanism for the inhibitory effect of Notch signaling on endothelial cell proliferation.
KW - Angiogensis
KW - Cell growth
KW - Cell signaling
UR - http://www.scopus.com/inward/record.url?scp=33845609555&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845609555&partnerID=8YFLogxK
U2 - 10.1096/fj.05-4880fje
DO - 10.1096/fj.05-4880fje
M3 - Article
C2 - 16571776
AN - SCOPUS:33845609555
SN - 0892-6638
VL - 20
SP - E201-E210
JO - FASEB Journal
JF - FASEB Journal
IS - 7
ER -