CK1ε and p120-catenin control Ror2 function in noncanonical Wnt signaling

Canonical and noncanonical Wnt pathways share some common elements but differ in the responses they evoke. Similar to Wnt ligands acting through the canonical pathway, Wnts that activate the noncanonical signaling, such as Wnt5a, promote Disheveled (Dvl) phosphorylation and its binding to the Frizzled (Fz) Wnt receptor complex. The protein kinase CK1 epsilon is required for Dvl/Fz association in both canonical and noncanonical signaling. Here we show that differently to its binding to canonical Wnt receptor complex, CK1 epsilon does not require p120-catenin for the association with the Wnt5a co-receptor Ror2. Wnt5a promotes the formation of the Ror2-Fz complex and enables the activation of Ror2-bound CK1 epsilon by Fz-associated protein phosphatase 2A. Moreover, CK1 epsilon also regulates Ror2 protein levels; CK1 epsilon association stabilizes Ror2, which undergoes lysosomal-dependent degradation in the absence of this kinase. Although p120-catenin is not required for CK1 epsilon association with Ror2, it also participates in this signaling pathway as p120-catenin binds and maintains Ror2 at the plasma membrane; in p120-depleted cells, Ror2 is rapidly internalized through a clathrin-dependent mechanism. Accordingly, downregulation of p120-catenin or CK1 epsilon affects late responses to Wnt5a that are also sensitive to Ror2, such as SIAH2 transcription, cell invasion, or cortical actin polarization. Our results explain how CK1 epsilon is activated by noncanonical Wnt and identify p120-catenin and CK1 epsilon as two critical factors controlling Ror2 function.