Regulation of Lrp6 phosphorylation.
The Wnt/beta-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis, and is implicated in human disease. Wnts transduce signals via transmembrane receptors of the Frizzled (Fzd/Fz) family and the low density lipoprotein receptor-related protein 5/6 (Lrp5/6). A key mechanism in their signal transduction is that Wnts induce Lrp6 signalosomes, which become phosphorylated at multiple conserved sites, notably at PPSPXS motifs. Lrp6 phosphorylation is crucial to beta-catenin stabilization and pathway activation by promoting Axin and Gsk3 recruitment to phosphorylated sites. Here, we summarize how proline-directed kinases (Gsk3, PKA, Pftk1, Grk5/6) and non-proline-directed kinases (CK1 family) act upon Lrp6, how the phosphorylation is regulated by ligand binding and mitosis, and how Lrp6 phosphorylation leads to beta-catenin stabilization.
Niehrs
Christof
C
Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 581, Heidelberg, Germany. niehrs@dkfz.de
Shen
Jinlong
J
D020816:Amino Acid Motifs; D000818:Animals; D005260:Female; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
D026502:LDL-Receptor Related Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051176:beta Catenin