Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling

Sara E.Konopelski Snavely, Michael W. Susman, Ryan C. Kunz, Jia Tan, Srisathya Srinivasan, Michael D. Cohen, Kyoko Okada, Helen Lamb, Shannon S. Choi, Edith P. Karuna, Michael K. Scales, Steven P. Gygi, Michael Eldon Greenberg, Hsin Yi Henry Ho

Research output: Contribution to journalArticlepeer-review

Abstract

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development [R. T. Moon et al., Development 119, 97-111 (1993); I. Oishi et al., Genes Cells 8, 645-654 (2003)], but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a β-catenin-independent, ubiquitinproteasome system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase kinase 3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, anotherWnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain [M. Flynn, O. Saha, P. Young, BMC Evol. Biol. 11, 235 (2011)], which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.

Original languageEnglish (US)
Article numbere2104944118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number25
DOIs
StatePublished - Jun 22 2021

Keywords

  • Pdzrn3
  • Ror1
  • Ror2
  • Wnt5a

ASJC Scopus subject areas

  • General

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