AMOT130 drives BMP-SMAD signaling at the apical membrane in polarized cells

Brunner, Patrizia; Haştar, Nurcan; Kaehler, Christian; Burdzinski, Wiktor; Jatzlau, Jerome; Knaus, Petra

doi:10.1091/mbc.e19-03-0179

Cited by 13 publications

(13 citation statements)

References 65 publications

(95 reference statements)

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“…The role of localized endocytosis and recycling of transmembrane and junction associated proteins has been demonstrated previously. For example, G protein-coupled receptor signaling (Weinberg and Puthenveedu, 2019 ) and several pathways controlled by AMOT, a cell junction associated signaling factor (Heller et al, 2010 ; Cox et al, 2015 ; Brunner et al, 2020 ), are regulated through locally concentrated endocytic activity. However, the activity of an endocytic cycle has not been shown previously to be associated with nuclear position.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Polarization of Rab11a Modulates Crb2a Localization and Impacts Signaling to Regulate Retinal Neurogenesis

Clark

Miesfeld

Flinn

et al. 2021

Front. Cell Dev. Biol.

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Interkinetic nuclear migration (IKNM) is the process in which pseudostratified epithelial nuclei oscillate from the apical to basal surface and in phase with the mitotic cycle. In the zebrafish retina, neuroepithelial retinal progenitor cells (RPCs) increase Notch activity with apical movement of the nuclei, and the depth of nuclear migration correlates with the probability that the next cell division will be neurogenic. This study focuses on the mechanisms underlying the relationships between IKNM, cell signaling, and neurogenesis. In particular, we have explored the role IKNM has on endosome biology within RPCs. Through genetic manipulation and live imaging in zebrafish, we find that early (Rab5-positive) and recycling (Rab11a-positive) endosomes polarize in a dynamic fashion within RPCs and with reference to nuclear position. Functional analyses suggest that dynamic polarization of recycling endosomes and their activity within the neuroepithelia modulates the subcellular localization of Crb2a, consequently affecting multiple signaling pathways that impact neurogenesis including Notch, Hippo, and Wnt activities. As nuclear migration is heterogenous and asynchronous among RPCs, Rab11a-affected signaling within the neuroepithelia is modulated in a differential manner, providing mechanistic insight to the correlation of IKNM and selection of RPCs to undergo neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Dynamic Polarization of Rab11a Modulates Crb2a Localization and Impacts Signaling to Regulate Retinal Neurogenesis

Clark

Miesfeld

Flinn

et al. 2021

Front. Cell Dev. Biol.

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“…However, our study on 2-adaptin showed no change in levels of endocytic proteins like Endo, Synj, and Dynamin [8]. Therefore, we sought to localizes to endosomes and is thought to modulate GTPase signaling [58]. Endocytic proteins appear to be fascinating candidates as BMP receptor interactors.…”

Section: Discussionmentioning

confidence: 94%

AP2 regulates Thickveins trafficking through Rab11 to attenuate NMJ growth signaling in Drosophila

Dwivedi

Choudhury

Patnaik

et al. 2021

Preprint

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Compromised endocytosis in neurons leads to synapse overgrowth and altered organization of synaptic proteins. However, the molecular players and the signaling pathways which regulate the process remains poorly understood. Here we show that σ2-adaptin, one of the subunits of the AP2-complex, genetically interacts with BMP type I receptor, Thickveins (Tkv), and Daughter against decapentaplegic (Dad), two of the components of BMP signaling. We found that mutations in σ2-adaptin lead to an accumulation of Tkv receptors at the NMJ and results in a significant reduction in Tkv-positive early endosomes in the presynaptic terminals. Interestingly, the level of small GTPase Rab11 was significantly reduced in the σ2-adaptin mutant synapses. Consistent with the role of σ2-adaptin and Rab11 in the regulation of the same signaling pathway, a mutation in Rab11 or overexpression of a GDP-locked form of Rab11 (Rab11S25N) phenocopies the morphological and signaling defects of the σ2-adaptin mutants. Finally, we demonstrate that σ2-adaptin mutants show an accumulation of large vesicles and massive membranous structures, akin to endosomes at the synapse. Thus, we propose a model in which AP2 regulates Tkv internalization and recycling through a process that requires Rab11 activity to control the synaptic growth.

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“…We recently revealed a key role for endogenous Amot in positively regulating egress and spread of PPxY-containing filoviruses (32, 33). Amotp130 contains multiple PPxY motifs that mediate interactions with WW-domains of YAP, BAG3, and WWOX (negative regulators of budding), and in doing so, function as a master regulator of several physiologically relevant pathways/processes, including transcription (Hippo pathway), actin polymerization, and tight junction (TJ) formation/integrity (45–54). Interestingly, stability and turnover of Amotp130 itself is tightly regulated by PPxY/WW-domain interactions with Nedd4 E3 ubiquitin ligase family members (positive regulators of budding) (58).…”

Section: Discussionmentioning

confidence: 99%

Angiomotin Counteracts the Negative Regulatory Effect of Host WWOX on Viral PPxY-Mediated Egress

Liang

Ruthel

Sagum

et al. 2021

Preprint

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Filoviridae family members Ebola (EBOV) and Marburg (MARV) viruses and Arenaviridae family member Lassa virus (LASV) are emerging pathogens that can cause hemorrhagic fever and high rates of mortality in humans. A better understanding of the interplay between these viruses and the host will inform about the biology of these pathogens, and may lead to the identification of new targets for therapeutic development. Notably, expression of the filovirus VP40 and LASV Z matrix proteins alone drives assembly and egress of virus-like particles (VLPs). The conserved PPxY Late (L) domain motifs in the filovirus VP40 and LASV Z proteins play a key role in the budding process by mediating interactions with select host WW-domain containing proteins that then regulate virus egress and spread. To identify the full complement of host WW-domain interactors, we utilized WT and PPxY mutant peptides from EBOV and MARV VP40 and LASV Z proteins to screen an array of GST-WW-domain fusion proteins. We identified WW domain-containing oxidoreductase (WWOX) as a novel PPxY-dependent interactor, and we went on to show that full-length WWOX physically interacts with eVP40, mVP40 and LASV Z to negatively regulate egress of VLPs and of a live VSV/Ebola recombinant virus (M40). Interestingly, WWOX is a versatile host protein that regulates multiple signaling pathways and cellular processes via modular interactions between its WW-domains and PPxY motifs of select interacting partners, including host angiomotin (AMOT). Notably, we demonstrated recently that expression of endogenous AMOT not only positively regulates egress of VLPs, but also promotes egress and spread of live EBOV and MARV. Toward the mechanism of action, we show that the competitive and modular interplay among WWOX-AMOT-VP40/Z regulates VLP and M40 virus egress. Thus, WWOX is the newest member of an emerging group of host WW-domain interactors (e.g. BAG3; YAP/TAZ) that negatively regulate viral egress. These findings further highlight the complex interplay of virus-host PPxY/WW-domain interactions and their potential impact on the biology of both the virus and the host during infection.Author SummaryFiloviruses (Ebola [EBOV] and Marburg [MARV]) and arenavirus (Lassa virus; LASV) are zoonotic, emerging pathogens that cause outbreaks of severe hemorrhagic fever in humans. A fundamental understanding of the virus-host interface is critical for understanding the biology of these viruses and for developing future strategies for therapeutic intervention. Here, we identified host WW-domain containing protein WWOX as a novel interactor with VP40 and Z, and showed that WWOX inhibited budding of VP40/Z virus-like particles (VLPs) and live virus in a PPxY/WW-domain dependent manner. Our findings are important to the field as they expand the repertoire of host interactors found to regulate PPxY-mediated budding of RNA viruses, and further highlight the competitive interplay and modular virus-host interactions that impact both the virus lifecycle and the host cell.

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AMOT130 drives BMP-SMAD signaling at the apical membrane in polarized cells

Cited by 13 publications

References 65 publications

Dynamic Polarization of Rab11a Modulates Crb2a Localization and Impacts Signaling to Regulate Retinal Neurogenesis

Dynamic Polarization of Rab11a Modulates Crb2a Localization and Impacts Signaling to Regulate Retinal Neurogenesis

AP2 regulates Thickveins trafficking through Rab11 to attenuate NMJ growth signaling in Drosophila

Angiomotin Counteracts the Negative Regulatory Effect of Host WWOX on Viral PPxY-Mediated Egress

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