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10.1016/j.jbc.2025.110682 http://scihub22266oqcxt.onion/10.1016/j.jbc.2025.110682 40914247!ä!40914247 Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=40914247&cmd=llinks): Failed to open stream: HTTP request failed! 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WNT7A/B assemble a GPR124-RECK-LRP5/6 co-receptor complex to activate beta-catenin signaling in brain endothelial cells |pdf=|usr=}}{{40914247}} gab.com Text WNT7A/B assemble a GPR124-RECK-LRP5/6 co-receptor complex to activate beta-catenin signaling in brain endothelial cells JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=40914247 #FOAvip WNT7A and WNT7B, secreted by neural cells, are essential regulators of developmental brain angiogenesis and blood-brain barrier integrity. In brain endothelial cells, WNT7 proteins activate beta-catenin signaling through the ligand-specific receptor complex GPR124-RECK and classical WNT receptors of the FZD and LRP families. Previous studies suggested that WNT7 isoforms assemble a GPR124-RECK-FZD-LRP5/6 multi-receptor complex for signaling. However, direct biochemical evidence for this complex and its signaling mechanisms remains elusive. Here, we investigated the formation and signaling mechanisms of WNT7 co-receptor complexes in brain endothelial cells using CRISPR/Cas9, biochemical analyses, and cell-based assays. Unexpectedly, cells with knockout of all FZD isoforms retained approximately 25% of WNT7 responsiveness, whereas classical WNT3A signaling was completely abolished. Similarly, knockout of all Dvl paralogs, key mediators of FZD signaling, preserved approximately 50% of WNT7 signaling activity but fully blocked WNT3A responses. In contrast, knockout of Gpr124, Reck, or Lrp5/6 completely abrogated WNT7 signaling. While both WNT7A and WNT3A triggered LRP6 phosphorylation, only WNT3A induced DVL2 phosphorylation. Biochemical analyses revealed WNT7-dependent recruitment of LRP5/6, but not FZD, to the GPR124-RECK heterodimer, forming a GPR124-RECK-WNT7-LRP5/6 complex. In GPR124-deficient cells, WNT7 proteins still assembled a RECK-WNT7-LRP5/6 core complex, yet this complex lacked signaling activity and LRP6 phosphorylation. Clustering of RECK-WNT7-LRP5/6 complexes with recombinant dimeric GPR124 ectodomain or a RECK antibody partially restored signaling, suggesting that GPR124 mediates formation of higher-order complexes. Our findings indicate that WNT7 signaling in brain endothelial cells is driven by distinct co-receptor complexes: a FZD-independent GPR124-RECK-LRP5/6 complex and FZD-dependent complexes that likely act in synergy. Twit Text FOAVip WNT7A/B assemble a GPR124-RECK-LRP5/6 co-receptor complex to activate beta-catenin signaling in brain endothelial cells ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=40914247 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=40914247 #FOAvip English Wikipedia <ref>{{Cite pmid|40914247}}</ref> WNT7A/B assemble a GPR124-RECK-LRP5/6 co-receptor complex to activate beta-catenin signaling in brain endothelial cells #MMPMID40914247 Heiden R; Hannig L; Kuo CJ; Ergun S; Braunger BM; Vallon M J Biol Chem 2025[Sep]; ä (ä): 110682 PMID40914247show ga WNT7A and WNT7B, secreted by neural cells, are essential regulators of developmental brain angiogenesis and blood-brain barrier integrity. In brain endothelial cells, WNT7 proteins activate beta-catenin signaling through the ligand-specific receptor complex GPR124-RECK and classical WNT receptors of the FZD and LRP families. Previous studies suggested that WNT7 isoforms assemble a GPR124-RECK-FZD-LRP5/6 multi-receptor complex for signaling. However, direct biochemical evidence for this complex and its signaling mechanisms remains elusive. Here, we investigated the formation and signaling mechanisms of WNT7 co-receptor complexes in brain endothelial cells using CRISPR/Cas9, biochemical analyses, and cell-based assays. Unexpectedly, cells with knockout of all FZD isoforms retained approximately 25% of WNT7 responsiveness, whereas classical WNT3A signaling was completely abolished. Similarly, knockout of all Dvl paralogs, key mediators of FZD signaling, preserved approximately 50% of WNT7 signaling activity but fully blocked WNT3A responses. In contrast, knockout of Gpr124, Reck, or Lrp5/6 completely abrogated WNT7 signaling. While both WNT7A and WNT3A triggered LRP6 phosphorylation, only WNT3A induced DVL2 phosphorylation. Biochemical analyses revealed WNT7-dependent recruitment of LRP5/6, but not FZD, to the GPR124-RECK heterodimer, forming a GPR124-RECK-WNT7-LRP5/6 complex. In GPR124-deficient cells, WNT7 proteins still assembled a RECK-WNT7-LRP5/6 core complex, yet this complex lacked signaling activity and LRP6 phosphorylation. Clustering of RECK-WNT7-LRP5/6 complexes with recombinant dimeric GPR124 ectodomain or a RECK antibody partially restored signaling, suggesting that GPR124 mediates formation of higher-order complexes. Our findings indicate that WNT7 signaling in brain endothelial cells is driven by distinct co-receptor complexes: a FZD-independent GPR124-RECK-LRP5/6 complex and FZD-dependent complexes that likely act in synergy. äWNT7A/B assemble a GPR124-RECK-LRP5/6 co-receptor complex to activate (epmc).pdf DeepDyve Pubget Overpricing