來自基因技術(shù)公司腫瘤生物與血管新生研究部,，Lexicon Pharmaceuticals公司的研究人員發(fā)現(xiàn)了Tspan12在視網(wǎng)膜血管生成過程中的重要作用,。這一研究成果公布在Cell雜志上。
Wnt受體Frizzled-4 (FZD4),，共受體LRP5,，或者配基Norrin的編碼基因發(fā)生突變會擾亂視網(wǎng)膜血管的發(fā)育，引起眼科疾?。╫phthalmic diseases）,，其中Norrin雖然與Wnts沒有結(jié)構(gòu)上的相關(guān)性，但是Norrin能與FZD4結(jié)合,，從而激活Wnt途徑,。
在這篇文章中，研究人員發(fā)現(xiàn)了一種重要的視網(wǎng)膜血管蛋白：四旋蛋白Tspan12,，這種蛋白在視網(wǎng)膜血管中表達,，在FZD，LRP5,，和Norrin突變小鼠中,，可以發(fā)現(xiàn)Tspan12擬表型缺失,。而且Tspan12也與LRP5，和Norrin存在遺傳相關(guān)性,。
進一步研究發(fā)現(xiàn),，Tspan12的過量表達能通過作用于Norrin受體復(fù)合物，極大增加Norrin/β-catenin的表達,，而不是如之前發(fā)現(xiàn)的,，促進Wnt/β-catenin的表達，并且Tspan12 siRNA能抑制的是Norrin的轉(zhuǎn)錄應(yīng)答,，而不是Wnt3A,。
這些研究成果說明TAPAN12的重要作用，與Norrin多聚物互作,，促進FZD4多聚物的形成,，以及提升相關(guān)信號途徑的生理水平。（生物谷Bioon.com）
生物谷推薦原始出處：
Cell, Volume 139,16 October 2009 doi:10.1016/j.cell.2009.07.048
TSPAN12 Regulates Retinal Vascular Development by Promoting Norrin- but Not Wnt-Induced FZD4/β-Catenin Signaling
Harald J. Junge1, Stacey Yang1, 5, Jeremy B. Burton1, 5, Kim Paes4, Xiao Shu1, 6, Dorothy M. French2, Mike Costa3, Dennis S. Rice4 and Weilan Ye1, ,
1 Tumor Biology and Angiogenesis Department, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
2 Pathology Department, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
3 Department of Cancer Targets, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
4 Ophthalmology Department, Lexicon Pharmaceuticals Inc., 8800 Technology Forest, The Woodlands, TX 77381-1160, USA
Mutations in the genes encoding the Wnt receptor Frizzled-4 (FZD4), coreceptor LRP5, or the ligand Norrin disrupt retinal vascular development and cause ophthalmic diseases. Although Norrin is structurally unrelated to Wnts, it binds FZD4 and activates the canonical Wnt pathway. Here we show that the tetraspanin Tspan12 is expressed in the retinal vasculature, and loss of Tspan12 phenocopies defects seen in Fzd4, Lrp5, and Norrin mutant mice. In addition, Tspan12 genetically interacts with Norrin or Lrp5. Overexpressed TSPAN12 associates with the Norrin-receptor complex and significantly increases Norrin/β-catenin but not Wnt/β-catenin signaling, whereas Tspan12 siRNA abolishes transcriptional responses to Norrin but not Wnt3A in retinal endothelial cells. Signaling defects caused by Norrin or FZD4 mutations that are predicted to impair receptor multimerization are rescued by overexpression of TSPAN12. Our data indicate that Norrin multimers and TSPAN12 cooperatively promote multimerization of FZD4 and its associated proteins to elicit physiological levels of signaling.
