Interaction between LRP5 and Frat1 mediates the activation of the Wnt canonical pathway.
Low density lipoprotein receptor-related protein 5 (LRP5) has been identified as a Wnt co-receptor involved in the activation of the beta-catenin signaling pathway. To improve our understanding of the molecular mechanisms by which LRP5 triggers the canonical Wnt signaling cascade, we have screened for potential partners of LRP5 using the yeast two-hybrid system and identified Frat1 as a protein interacting with the cytoplasmic domain of LRP5. We demonstrate here that LRP5/Frat1 interaction is involved in beta-catenin nuclear translocation and TCF-1 transcriptional activation. The addition of Wnt3a or overexpression of constitutively active truncated LRP5 (LRP5C) induces Frat1 recruitment to the cell membrane. Overexpression of a dominant negative form of disheveled (Dvl) shows that this protein positively affects LRP5/Frat1 interaction. Furthermore, the fact that dominant negative Dvl does not interfere with LRP5C/Frat1 interaction can explain how LRP5C is capable of acting independently of this major Wnt signaling player. Axin, which has been shown to interact with LRP5 and to be recruited to the membrane through this interaction, was found to co-immunoprecipitate with Frat1 and LRP5. We propose that recruitment of Axin and Frat1 to the membrane by LRP5 leads to both Axin degradation and Frat1-mediated inhibition of glycogen synthase kinase-3. As a consequence, beta-catenin is no longer bound to Axin or phosphorylated by glycogen synthase kinase-3, resulting in TCF-1 activation.
Hay
Eric
E
Proskelia Pharmaceuticals, 102 route de Noisy, 93230 Romainville, France.
Faucheu
Chi
C
Suc-Royer
Isabelle
I
Touitou
Robert
R
Stiot
Veronique
V
Vayssière
Béatrice
B
Baron
Roland
R
Roman-Roman
Sergio
S
Rawadi
Georges
G
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D060466:Axin Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000072261:Dishevelled Proteins; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D002352:Carrier Proteins; D000072261:Dishevelled Proteins; C491818:Frat1 protein, mouse; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse