Dickkopf related protein 4 (Dkk-4) is a member of the Dkk protein family of secreted Wnt antagonists. Dkk-1 and Dkk-4 antagonize Wnt/beta-catenin signaling by direct high affinity binding to the Wnt coreceptor LRP5/6 and inhibiting interaction of LRP5/6 with the Wnt-Frizzled complex. Dkk-1 and Dkk-4 also bind the transmembrane proteins Kremen-1 and Kremen-2 with high affinity. Kremen-2 can form a ternary complex with Dkk-1 or Dkk-4 plus LRP5/6 to trigger internalization of the complex and removal of LRP6 from the cell surface. Thus, Dkk-1/4 and Kremens function synergistically to antagonize LRP5/6-mediated Wnt activity.