Skip to main content
. 2021 Apr 29;22(9):4690. doi: 10.3390/ijms22094690

Figure 2.

Figure 2

LGR4-induced Wnt/β-catenin signaling pathway. (a) RSPOs are a family of secreted proteins that can activate LGR4-induced Wnt/β-catenin signaling. Structurally, all the RSPOs have a signal peptide in the N-terminal domain, two furin-like cysteine-rich domains, a thrombospondin 1 repeat domain (TSR), and a basic amino acid-rich domain, which varies in size according to the RSPO member (b) In the absence of RSPO, ZNF3/RNF43 ubiquitinates the frizzled (Fzd)/LRP5-6 receptor complex for degradation. Wnt signal is blocked and the β-catenin destruction complex (formed by CK1, GSK3β, APC, and AXIN) is activated. GSK3β and CK1 phosphorylate β-catenin, inducing its ubiquitination and consequent proteasomal degradation. When LGR4 is activated by RSPOs, Norrin, or circLGR4 ligands, it stabilizes the frizzled/Lrp5-6 complex in the membrane, avoiding its degradation by inhibiting the activity of ZNRF3 and RNF43 proteins. Furthermore, LGR4 recruits IQGAP1 with an increasing affinity for DVL and recruits MEK, which phosphorylates LRP5/6, leading to the recruitment and inhibition of the β-catenin destruction complex into the Fzd/Lrp5-6 complex receptor.