Recombinant Human LRP-6 Fc Chimera Protein, CF

The low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) and LRP6 constitute a distinct subgroup of the LDL receptor family. Both LRP5 and LRP6 are type I transmembrane proteins that function as co-receptors with Frizzled (FZD) in the canonical Wnt signaling pathway (1, 2). LRP6 cDNA encodes a 1613 amino acid residue (aa) precursor with a 19 aa signal sequence, a 1353 aa extracellular region, a 23 aa transmembrane (TM) segment and a 218 aa cytoplasmic domain (3). The extracellular region contains four N-terminal cysteine-rich EGF-like repeats, followed by three cysteine-rich LDLR repeats. This pattern of the EGF and LDLR repeat arrangement is different than that typically found in other LDL receptor family proteins. The intracellular region of LRP6 contains protein-protein interaction motifs and is required for canonical Wnt signal transduction (4). Human LRP-6 shares 98% and 74% aa sequence identity with mouse LRP-6 and human LRP-5, respectively. Based on the current model, canonical Wnt signaling requires the interaction of Wnt with FZD and LRP to form a trimeric complex which signals downstream to stabilize cytoplasmic  beta -catenin. The stabilized beta -catenin is then translocated to the nucleus where it complexes with the transcription factor LEF/TCF to regulate the transcription of target genes (5). LRP6 has also been shown to interact with the Dickkopf proteins (DKKs), which are modulators of Wnt signaling (6 - 8). Binding of DKK-1 to LRP6 dissociates LRP6 from FZD, and antagonizes the formation of the functional receptor complex. On cells where the transmembrane proteins Kremens are also present, a ternary complex of LRP6, DKK-1 and Kremen is formed to trigger the internalization of the complex and removal LRP6 from the cell surface. Thus, DKK-1 and Kremen function synergistically to antagonize LRP6-mediated Wnt activity. Although DKK-2 also functions as a Wnt antagonist on cells that express Kremen, DKK-2 binding to LRP-6 in the absence of Kremen activates rather than inhibits LRP mediated beta -catenin signaling (9, 10).