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Beschreibung

Low-density lipoprotein receptor-related protein 6 (UniProt: also known as LRP-6) is encoded by the LRP6 gene (Gene ID: 4040) in human. LRP-6 is a disulfide-linked homodimeric, single-pass type I transmembrane protein, which is a component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling. LRP-6 is widely co-expressed with LRP5 during embryogenesis and in adult tissues and its levels decrease upon Wnt3A stimulation. It is synthesized with a signal peptide (aa 1-19), which is cleaved off in the mature form. LRP-6 has an extracellular domain (aa 20-1370), a short helical transmembrane domain (aa 1371-1393), and a cytoplasmic tail (aa 1394-1613). LRP-6 contains five PPPSP motifs that play a central role in signal transduction following phosphorylation and activation of Wnt signaling pathway. Dual phosphorylation of cytoplasmic PPPSP motifs sequentially by GSK3 and CK1 is shown to be essential for AXIN1-binding, and subsequent stabilization and activation of beta-catenin via preventing GSK3-mediated phosphorylation of beta-catenin. Upon Wnt signaling, LRP-6 is shown to undergo a cycle of caveolin- or clathrin-mediated endocytosis and plasma membrane location and it undergoes phosphorylation, aggregation, and co-localization with AXIN1 and GSK-3beta at the plasma membrane in LRP-6 signalsomes. It is released from the endoplasmic reticulum following palmitoylation. On two sites near the transmembrane domain. However, in the absence of palmitoylation mono-ubiquitination retains it in the endoplasmic reticulum. Threonine1479 of LRP-6 is phosphorylated by casein kinase I (CK1) and this phosphorylation is facilitated by TMEM198. (Ref.: Liang, J., et al. (2011). Mol. Cell Biol. 31(13), 2577-2590).