Low-density lipoprotein receptor-related protein 6 (LRP6) is a component of cell-surface receptors for Writ proteins and Writ is known to promote recruitment of Axin by LRP6 thereby inhibiting P-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 Writ 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 P-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 Writ 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 Writ signaling. (c) 2007 Elsevier Inc. All rights reserved.