Wise retained in the endoplasmic reticulum inhibits Wnt signaling by reducing cell surface LRP6.
The Wnt signaling pathway is tightly regulated by extracellular and intracellular modulators. Wise was isolated as a secreted protein capable of interacting with the Wnt co-receptor LRP6. Studies in Xenopus embryos revealed that Wise either enhances or inhibits the Wnt pathway depending on the cellular context. Here we show that the cellular localization of Wise has distinct effects on the Wnt pathway readout. While secreted Wise either synergizes or inhibits the Wnt signals depending on the partner ligand, ER-retained Wise consistently blocks the Wnt pathway. ER-retained Wise reduces LRP6 on the cell surface, making cells less susceptible to the Wnt signal. This study provides a cellular mechanism for the action of Wise and introduces the modulation of cellular susceptibility to Wnt signals as a novel mechanism of the regulation of the Wnt pathway.
Guidato
Sonia
S
Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
Itasaki
Nobue
N
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051155:Wnt1 Protein / Q000378:metabolism*; D060508:Wnt3 Protein; D014982:Xenopus laevis / Q000378:metabolism*
D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein