LRP6 lets Merlin go in times of nutrient scarcity

Abstract

Cells take advantage of cross-talk in signaling pathways to integrate diverse signals and produce coordinated responses. In this issue of EMBO Reports, Jeong et al discover that the Wnt co-receptor, low-density lipoprotein (LDL) receptor-related protein LRP6, negatively regulates Hippo signaling by serving as a binding sink to sequester and inhibit Merlin, an activator of Hippo signaling (Jeong et al, 2020). This regulation is nutrient-responsive, likely using LRP6 O-GlcNAcylation as a molecular switch.

Figure 1. Wnt co‐receptor LRP6 serves as a binding sink to sequester and inhibit Merlin

When nutrients are abundant (left), LRP6 is O‐GlcNAcylated by OGT and sequesters Merlin. Hippo signaling remains inactive (YAP is active). Upon starvation (right), OGT no longer translocates to the plasma membrane. LRP6 becomes less O‐GlcNAc modified and is subject to downregulation. Released from LRP6, Merlin binds to LATS1/2 and promotes LATS1/2 activation (which inactivates YAP).