Recombinant Rat Kremen-2 Protein, CF

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 with no conserved motifs (1). Two related molecules, Kremen-1 and -2, have been identified. Kremens bind with high affinity to a subset of the secreted Dickkopf proteins (Dkk-1, -2, and -4) to modulate the canonical Wnt signaling pathway (2). This pathway is transduced by a ternary receptor complex composed of Wnt, the seven-transmembrane domain receptor Frizzled, and the LDL-receptor-related protein 5/6 (LRP5/6) coreceptor (3, 4). Dkk-1 and -4 bind directly to the LRP5/6 coreceptor to antagonize the canonical Wnt/ beta-catenin signaling pathway. The planar cell polarity (PCP) signaling pathway is not affected as it does not involve LRP5/6 (2). In contrast, Dkk-3 has no effect on Wnt signaling. Dkk-2 can function either as an LRP agonist or antagonist, depending on whether or not the cell expresses Kremen (5). Kremen cooperates with Dkk to antagonize Wnt signaling via formation of a Kremen-Dkk-LRP ternary complex which is internalized and cleared from the cell surface (4). Binding requires all three extracellular domains of Kremen, and the second cysteine-rich domain of Dkk (4). The predicted rat Kremen-2 cDNA encodes a 490 amino acid (aa) glycosylated protein with a 51 aa signal peptide, a 340 aa extracellular domain, a 24 aa transmembrane domain, and a 75 aa cytoplasmic domain. Within the ECD, rat Kremen-2 shares 91% and 98% aa sequence identity with human and mouse Kremen-2, respectively, and 46% with rat Kremen-1.