Zebrafish G protein gamma2 is required for VEGF signaling during angiogenesis.
Vascular endothelial growth factor (VEGF) is a major mediator of pathologic angiogenesis, a process necessary for the formation of new blood vessels to support tumor growth. Historically, VEGF has been thought to signal via receptor tyrosine kinases, which are not typically considered to be G protein dependent. Here, we show that targeted knockdown of the G protein gng2 gene (Ggamma2) blocks the normal angiogenic process in developing zebrafish embryos. Moreover, loss of gng2 function inhibits the ability of VEGF to promote the angiogenic sprouting of blood vessels by attenuating VEGF induced phosphorylation of phospholipase C-gamma1 (PLCgamma1) and serine/threonine kinase (AKT). Collectively, these results demonstrate a novel interaction between Ggamma2- and VEGF-dependent pathways to regulate the angiogenic process in a whole-animal model. Blocking VEGF function using a humanized anti-VEGF antibody has emerged as a promising treatment for colorectal, non-small lung cell, and breast cancers. However, this treatment may cause considerable side effects. Our findings provide a new opportunity for cotargeting G protein- and VEGF-dependent pathways to synergistically block pathologic angiogenesis, which may lead to a safer and more efficacious therapeutic regimen to fight cancer.
Leung
Tinchung
T
Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA.
Chen
Hui
H
Stauffer
Anna M
AM
Giger
Kathryn E
KE
Sinha
Soniya
S
Horstick
Eric J
EJ
Humbert
Jasper E
JE
Hansen
Carl A
CA
Robishaw
Janet D
JD
D000818:Animals; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D020869:Gene Expression Profiling; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D010641:Phenotype; D051966:Phospholipase C gamma / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology
C521906:G protein gamma2, zebrafish; D044388:GTP-Binding Protein gamma Subunits; D021122:Protein Subunits; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D051057:Proto-Oncogene Proteins c-akt; D051966:Phospholipase C gamma; D019204:GTP-Binding Proteins