Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling
Abstract Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development, 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, ubiquitin-proteasome system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, CK1, and GSK3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain, 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 new Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 30. Okt. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Konopelski Snavely, Sara E. [VerfasserIn] |
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| doi: |
10.1101/2020.06.22.163790 |
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| PPN (Katalog-ID): |
XBI01819074X |
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| 245 | 1 | 0 | |a Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling |
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| 520 | |a Abstract Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development, 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, ubiquitin-proteasome system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, CK1, and GSK3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain, 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 new Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
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| 700 | 1 | |a Susman, Michael W. |e verfasserin |4 aut | |
| 700 | 1 | |a Kunz, Ryan C. |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Srinivasan, Srisathya |e verfasserin |4 aut | |
| 700 | 1 | |a Cohen, Michael D. |e verfasserin |4 aut | |
| 700 | 1 | |a Okada, Kyoko |e verfasserin |4 aut | |
| 700 | 1 | |a Lamb, Helen |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Shannon S. |e verfasserin |4 aut | |
| 700 | 1 | |a Karuna, Edith P. |e verfasserin |4 aut | |
| 700 | 1 | |a Scales, Michael K. |e verfasserin |4 aut | |
| 700 | 1 | |a Gygi, Steven P. |e verfasserin |4 aut | |
| 700 | 1 | |a Greenberg, Michael E. |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Hsin-Yi Henry |e verfasserin |4 aut | |
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