GRB10 binds to LRP6, the Wnt co-receptor and inhibits canonical Wnt signaling pathway.
Low-density lipoprotein receptor-related protein 6 (LRP6) is a component of cell-surface receptors for Wnt proteins and Wnt is known to promote recruitment of Axin by LRP6 thereby inhibiting beta-catenin's degradation. We show here that growth factor receptor-bound protein10 (GRB10), a multi-modular adaptor protein that is known to associate with several transmembrane tyrosine kinase receptors, binds to the intracellular portion of LRP6 and negatively regulates Wnt signaling. GRB10 overexpression suppressed Wnt3a-, and LRP6-induced but not beta-catenin-induced TCF-dependent-reporter activities in HEK293T cells, suggesting that GRB10 functions upstream of beta-catenin. Actually, GRB10 overexpression attenuated the Wnt3a-induced accumulation of beta-catenin. In addition, RNAi-mediated down-regulation of endogenous GRB10 stimulated Wnt3a-induced reporter activities, indicating that GRB10 is indeed a novel negative regulator of the Wnt signaling pathway. The finding that GRB10 interferes with the binding of Axin to LRP6 indicated a possible molecular mechanism by which the overexpression of GRB10 suppresses Wnt signaling.
Tezuka
Norio
N
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-Ku, Kyoto 606-8507, Japan.
Brown
Anthony M C
AM
Yanagawa
Shin-ichi
S
D000818:Animals; D060466:Axin Protein; D001665:Binding Sites; D051383:GRB10 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D034622:RNA Interference; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors; D018909:src Homology Domains / Q000502:physiology
D060466:Axin Protein; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D011973:Receptors, LDL; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D051383:GRB10 Adaptor Protein