Kremen (Kringle-containing protein marking the eye and the nose) proteins are type I transmembrane proteins that contain extracellular kringle, WSC and CUB domains and an intracellular region without any conserved motifs (1). Two related members, Kremen-1 and -2, have been identified. Kremens bind a subset of the secreted Dickkopf (Dkk) proteins (Dkk-1, -2, and -4) with high affinity to modulate the canonical Wnt signaling pathway that is transduced by the ternary receptor complex composed of Wnt, the seven-transmembrane domain receptor Frizzled, and the LDL-receptor-related protein 5/6 (LRP5/6) coreceptor (2, 3). Within the Dkk family, Dkk-1 and -4 bind directly to the LRP5/6 coreceptor to antagonize the canonical Wnt/ beta -catenin signaling pathway, but not the planar cell polarity (PCP) signaling pathway that does not involve LRP5/6 (4). In contrast, Dkk-3 has no effect on Wnt signaling and Dkk-2 can function either as an LRP agonist or antagonist, depending on whether the cell expresses Kremen (5). Kremen cooperates with Dkk to antagonize Wnt signaling via formation of a Kremen-Dkk-LRP ternary complex that triggers the internalization and clearance of the complex from the cell surface (3). All three extracellular domains but not the cytoplasmic region of a membrane anchored Kremen are needed for binding to the second cysteine-rich domain of Dkks (3). Mouse Kremen-2 cDNA encodes a 461 amino acid (aa) glycosylated protein with a putative 24 aa signal peptide, a 339 aa extracellular domain, a 23 aa transmembrane domain and a 75 aa cytoplasmic domain. In the extracellular domain, it shares 88% and 41% amino acid sequence identity with human Kremen-2 and mouse Kremen-1, respectively.