Transcription factor 8 activates R-Ras to regulate angiogenesis.
We have recently reported that transcription factor 8 (TCF8) negatively regulates pathological angiogenesis by regulating endothelial invasiveness by acting as a transcriptional attenuator of matrix metalloproteinase 1. TCF8 also modulates cell-matrix and cell-cell adhesion; however molecular mechanism of this TCF8 function remains obscure. Here, we provide evidence that TCF8 activates R-Ras, another class of angiogenic regulator, to suppress angiogenesis by a mechanism other than a transcriptional attenuator. Tube formation by human umbilical vein endothelial cells (HUVECs) facilitated by TCF8 suppression was significantly inhibited by the expression of constitutive active mutant of R-Ras. When we examined the mRNA expression levels of R-Ras regulators, no significant changes were observed to explain the R-Ras activation by TCF8. Interestingly, we found that TCF8 bound to CalDAG-GEFIII, an R-Ras activator, in the cytosol, indicating that TCF8 emanates signaling for R-Ras activation from cytosol to regulate angiogenesis negatively.
Inuzuka
Takayuki
T
Laboratory of Pathophysiology and Signal Transduction, Hokkaido University, Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Tsuda
Masumi
M
Kawaguchi
Hideaki
H
Ohba
Yusuke
Y
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000201:enzymology; D000071799:Zinc Finger E-box-Binding Homeobox 1; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D018398:Homeodomain Proteins; C413212:RASGRP3 protein, human; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins