Regulation of Wnt/PCP signaling through p97/VCP-KBTBD7–mediated Vangl ubiquitination and endoplasmic reticulum–associated degradation

Feng, Di; Wang, Jin; Yang, Wei; Li, Jingyu; Lin, Xiaochen; Zha, Fangzi; Wang, Xiaolu; Ma, Luyao; Choi, Nga Ting; Mii, Yusuke; Takada, Shinji; Huen, Michael S.Y.; Guo, Yusong; Zhang, Liang; Gao, Bo

doi:10.1126/sciadv.abg2099

Cited by 35 publications

(28 citation statements)

References 83 publications

(146 reference statements)

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“…Our results suggest that the substrate-ubiquitinating Mib1 RING-finger domains are required for PCP. As Ubiquitin-dependent membrane trafficking is important for PCP ( Butler and Wallingford, 2017 ; Devenport, 2014 ; Feng et al, 2021 ), we set out to determine whether Mib1 controls CE by regulating the trafficking of a PCP pathway component.…”

Section: Resultsmentioning

confidence: 99%

The E3 ubiquitin ligase mindbomb1 controls planar cell polarity-dependent convergent extension movements during zebrafish gastrulation

Saraswathy

Kurup

Sharma

et al. 2022

eLife

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Vertebrate Delta/Notch signaling involves multiple ligands, receptors and transcription factors. Delta endocytosis - a critical event for Notch activation - is however essentially controlled by the E3 Ubiquitin ligase Mindbomb1 (Mib1). Mib1 inactivation is therefore often used to inhibit Notch signaling. However, recent findings indicate that Mib1 function extends beyond the Notch pathway. We report a novel Notch-independent role of Mib1 in zebrafish gastrulation. mib1 null mutants and morphants display impaired Convergence Extension (CE) movements. Comparison of different mib1 mutants and functional rescue experiments indicate that Mib1 controls CE independently of Notch. Mib1-dependent CE defects can be rescued using the Planar Cell Polarity (PCP) downstream mediator RhoA, or enhanced through knock-down of the PCP ligand Wnt5b. Mib1 regulates CE through its RING Finger domains that have been implicated in substrate ubiquitination, suggesting that Mib1 may control PCP protein trafficking. Accordingly, we show that Mib1 controls the endocytosis of the PCP component Ryk and that Ryk internalization is required for CE. Numerous morphogenetic processes involve both Notch and PCP signaling. Our observation that during zebrafish gastrulation Mib1 exerts a Notch-independent control of PCP-dependent CE movements suggest that Mib1 loss of function phenotypes should be cautiously interpreted depending on the biological context.

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Section: Resultsmentioning

confidence: 99%

The E3 ubiquitin ligase mindbomb1 controls planar cell polarity-dependent convergent extension movements during zebrafish gastrulation

Saraswathy

Kurup

Sharma

et al. 2022

eLife

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“…Both Vangls have conserved basolateral-sorting motifs (YXXF) critical for the recruitment of Vangl into transport vesicles, and proper cell membrane localization of Vangl ( Guo et al, 2013 ; Iliescu and Gros, 2014 ). More recently, a p97/VCP-interacting motif (VIM motif) was identified in the C-terminal of Vangl2 that is required for direct interactions between Vangl2 and p97/VCP, a chaperone-related ATPase, which is critical for ubiquitination and degradation of Vangl through the endoplasmic reticulum-associated degradation (ERAD) pathway ( Feng et al, 2021 ). The C-terminal tail of Vangl also contains a Prickle binding domain (PkBD) that facilitates interactions between Vangl and the cytosolic effector Pk ( Nagaoka et al, 2019 ).…”

Section: Vangl Structure Promotes Assembly Of Diverse Binding Partnersmentioning

confidence: 99%

“…A recent study identified a novel post-translational mechanism for regulating Vangl protein levels. Feng et al (2021) determined that Vangl2 proteins are basally phosphorylated in the ER prior to being transported to the cell membrane. Vangl2 proteins lacking basal phosphorylation are marked for endoplasmic reticulum-associated protein degradation (ERAD).…”

Section: Proper Localization Of Vangl Is Critical For Functionmentioning

confidence: 99%

Vangl as a Master Scaffold for Wnt/Planar Cell Polarity Signaling in Development and Disease

Dreyer

VanderVorst

Carraway

2022

Front. Cell Dev. Biol.

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The establishment of polarity within tissues and dynamic cellular morphogenetic events are features common to both developing and adult tissues, and breakdown of these programs is associated with diverse human diseases. Wnt/Planar cell polarity (Wnt/PCP) signaling, a branch of non-canonical Wnt signaling, is critical to the establishment and maintenance of polarity in epithelial tissues as well as cell motility events critical to proper embryonic development. In epithelial tissues, Wnt/PCP-mediated planar polarity relies upon the asymmetric distribution of core proteins to establish polarity, but the requirement for this distribution in Wnt/PCP-mediated cell motility remains unclear. However, in both polarized tissues and migratory cells, the Wnt/PCP-specific transmembrane protein Vangl is required and appears to serve as a scaffold upon which the core pathway components as well as positive and negative regulators of Wnt/PCP signaling assemble. The current literature suggests that the multiple interaction domains of Vangl allow for the binding of diverse signaling partners for the establishment of context- and tissue-specific complexes. In this review we discuss the role of Vangl as a master scaffold for Wnt/PCP signaling in epithelial tissue polarity and cellular motility events in developing and adult tissues, and address how these programs are dysregulated in human disease.

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“…Previous studies have revealed the extensive role of VCP in SG clearance. Disease-related VCP mutants significantly impair SG disassembly and lead to elevated oxidative stress in an animal model. ,, Considering that VCP is an important node in the endoplasmic reticulum-associated degradation (ERAD) pathway , and that the regulation of cellular condensate dynamics is tightly related to ER membrane contact sites, an intriguing hypothesis is that the clearance of intracellular condensates, including SGs, may share some common pathways with the ERAD system. In addition, ALS-related mutations can disrupt the autophagy-mediated disassembly of “chronic SGs”.…”

Section: Deficiency In the Clearance Of Stress-induced Condensates Ex...mentioning

confidence: 99%

Stress Granule Homeostasis, Aberrant Phase Transition, and Amyotrophic Lateral Sclerosis

Liu

2022

ACS Chem. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, a large number of ALS-related mutations have been discovered to have a strong link to stress granules (SGs). SGs are cytoplasmic ribonucleoprotein condensates mediated by liquid−liquid phase separation (LLPS) of biomacromolecules. They help cells cope with stress. The normal physiological functions of SGs are dependent on three key aspects of SG "homeostasis": SG assembly, disassembly, and SG components. Any of these three aspects can be disrupted, resulting in abnormalities in the cellular stress response and leading to cytotoxicity. Several ALS-related pathogenic mutants have abnormal LLPS abilities that disrupt SG homeostasis, and some of them can even cause aberrant phase transitions. As a result, ALS-related mutants may disrupt various aspects of SG homeostasis by directly disturbing the intermolecular interactions or affecting core SG components, thus disrupting the phase equilibrium of the cytoplasm during stress. Considering that the importance of the "global view" of SG homeostasis in ALS pathogenesis has not received enough attention, we first systematically summarize the physiological regulatory mechanism of SG homeostasis based on LLPS and then examine ALS pathogenesis from the perspective of disrupted SG homeostasis and aberrant phase transition of biomacromolecules.

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Regulation of Wnt/PCP signaling through p97/VCP-KBTBD7–mediated Vangl ubiquitination and endoplasmic reticulum–associated degradation

Cited by 35 publications

References 83 publications

The E3 ubiquitin ligase mindbomb1 controls planar cell polarity-dependent convergent extension movements during zebrafish gastrulation

The E3 ubiquitin ligase mindbomb1 controls planar cell polarity-dependent convergent extension movements during zebrafish gastrulation

Vangl as a Master Scaffold for Wnt/Planar Cell Polarity Signaling in Development and Disease

Stress Granule Homeostasis, Aberrant Phase Transition, and Amyotrophic Lateral Sclerosis

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