Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling
Sara E. Konopelski, Michael W. Susman, Ryan C. Kunz, Jia Tan, Srisathya Srinivasan, Michael D. Cohen, Kyoko Okada, Helen Lamb, S. S. Choi, Edith P. Karuna, Michael K. Scales, Steven P. Gygi, Michael E. Greenberg, Hsin‐Yi Henry Ho
Abstract
Significance Wnt5a-Ror signaling is a master regulator of tissue shape, and dysfunction of the pathway contributes to congenital birth defects and cancer metastasis. The molecular underpinnings of this pathway, however, remain unclear. To identify subcellular protein changes driven by Wnt5a-Ror signaling, we conducted a large-scale proteomic screen and identified the E3 ubiquitin ligase Pdzrn3 as a downstream target. Wnt5a-Ror signaling initially induces Pdzrn3 phosphorylation, which subsequently triggers the ubiquitin-proteasome–dependent degradation of Pdzrn3. Importantly, Wnt5a-Ror signaling uses this phospho-degradation process to regulate cell migration. From these findings, we further developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated the signaling cascade regulating Pdzrn3 stability. Collectively, our study establishes Pdzrn3 phosphorylation and degradation as a key component of Wnt5a-Ror signaling.