Removing the Receptor to Inhibit Wnt Signaling

Mao et al. isolated a binding partner for the Wnt signaling inhibitor Dickkopf1 (Dkk1) by expression cloning. This binding partner was a member of the Kremen family of transmembrane proteins, and subsequent analysis showed that Dkk1 and Dkk2 both bound to Kremen1 and Kremen2. Contransfection of Dkk1 and Kremen1 or Kremen2 inhibited Wnt signaling measured as change in reporter gene expression. Wnt signaling is initiated by interactions with two receptors: Frizzled and LRPS or LRPG. Dkk1 promoted the interaction of Kremen2 with LPR6, and in transfected cells, Dkk stimulated the endocytosis of LRP6 and Dkk1. Thus, Dkk proteins may inhibit Wnt signaling by stimulating the removal of one of the Wnt receptor partners from the cell surface. B. Mao, W. Wu, G. Davidson, J. Marhold, M. Li, B. M. Mechler, H. Dellus, D. Hoppe, P. Stannek, C. Walter, A. Glinka, C. Niehrs, Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling. Nature 417 , 664-667 (2002). [Online Journal]