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Mechanisms of Wnt5a‐Ror Signaling in Development and Disease
Author(s) -
Ho Henry,
Konopelski Sara,
Susman Michael,
Kunz Ryan,
Tan Jia,
Cohen Michael,
Okada Kyoko,
Lamb Helen,
Choi Shan,
Karuna Edith,
Scales Michael,
Gygi Steven,
Greenberg Michael
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00207
Subject(s) - dishevelled , wnt5a , frizzled , microbiology and biotechnology , signal transduction , ubiquitin , biology , phosphorylation , casein kinase 1 , ubiquitin ligase , mg132 , gsk 3 , wnt signaling pathway , proteasome , genetics , protein kinase a , gene , proteasome inhibitor
Wnt5a‐Ror signaling is a conserved developmental pathway that regulates morphogenetic processes during vertebral embryonic development, and dysfunction of the pathway causes a number of human disorders, including Robinow syndrome. The mechanisms of Wnt5a‐Ror signaling remain poorly understood. Using a large‐scale proteomic screen, we identified the E3 ubiquitin ligase Pdzrn3 as a new regulatory target that is degraded upon pathway activation in a beta‐catenin independent, ubiquitin‐proteasome system dependent manner. Using this discovery, 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 degradation. Genetic epistasis analysis suggests that Pdzrn3 resides downstream of Dishevelled and independently of Kif26b, a previously identified Wnt5a‐Ror regulatory target. Further, we discovered that Pdzrn3 degradation requires Wnt5a‐dependent phosphorylation of its C‐terminal LNX3H domain, which is conserved in several Pdzrn3 homologs and likely functions as a novel Wnt5a‐responsive domain. Collectively, this work establishes a new Wnt5a‐Ror signaling cascade involving Pdzrn3 phosphorylation and degradation. Support or Funding Information NIH Grant 1R35GM119574