Sprouty4 deficiency potentiates Ras-independent angiogenic signals and tumor growth.
Sprouty proteins have been shown to negatively regulate a variety of receptor tyrosine kinase (RTK) signaling pathways and are considered to be tumor suppressor proteins. The pathophysiological functions of Sproutys in vivo remain to be investigated. In this study, we examined the physiological function of Sprouty4 as an angiogenic regulator, using Sprouty4 knockout (KO) mice and cells. We found that transplanted tumor cells grow much faster in Sprouty4 KO mice than in wild type (WT) mice, which we associate with enhanced neovascularization in the tumors transplanted into Sprouty4 KO mice. Moreover, vascular endothelial growth factor (VEGF)-A-induced angiogenesis and vascular permeability in vivo were enhanced in Sprouty4 KO mice compared with WT mice. Ex vivo angiogenesis, which we induced by VEGF-A, basic fibroblast growth factor (bFGF), and sphingosine-1-phosphate (S1P), was also enhanced in the aortas of Sprouty4 KO mice. We demonstrated that Sprouty4 suppresses Ras-independent VEGF-A and S1P signaling, while it does not affect Ras-dependent VEGF-C signaling. These data indicate that Sprouty4 selectively suppresses Ras-independent angiogenic factor signals and is an important negative regulator of pathophysiological angiogenesis.
Taniguchi
Koji
K
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Ishizaki
Takuma
T
Ayada
Toranoshin
T
Sugiyama
Yuki
Y
Wakabayashi
Yu
Y
Sekiya
Takashi
T
Nakagawa
Ryusuke
R
Yoshimura
Akihiko
A
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000473:pathology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism*
D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; C499037:Spry4 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; C060506:sphingosine 1-phosphate; D008156:Luciferases; D018631:ras Proteins; D013110:Sphingosine