The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation

Wang, Chenji; An, Jian; Zhang, Pingzhao; Xu, Chen; Gao, Kun; Wu, Di; Wang, Dejie; Yu, Hongxiu; Liu, Jun O.; Liu, Yu

doi:10.1042/bj20111983

Cited by 68 publications

(84 citation statements)

References 22 publications

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“…Other interesting findings in this study were that IL-6 participated in E3 ubiquitin ligase Ubr 1 expression and the consequent activation of ubiquitin proteasome and degradation of ZO-1 in brain microvascular endothelial cells. E3 ubiquitin ligases such as Itch and Nedd4 are involved in the proteasomal degradation of cytoplasmic proteins, including occludin (43,44). Evidence suggests that the expression of Ubr 1 is dependent on the STAT activity induced by the IL-6/gp130 signaling pathway (32,45).…”

Section: Discussionmentioning

confidence: 99%

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Chen

et al. 2014

J Virol

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h Though the compromised blood-brain barrier (BBB) is a pathological hallmark of Japanese encephalitis-associated neurological sequelae, the underlying mechanisms and the specific cell types involved are not understood. BBB characteristics are induced and maintained by cross talk between brain microvascular endothelial cells and neighboring elements of the neurovascular unit. In this study, we show a potential mechanism of disruption of endothelial barrier integrity during the course of Japanese encephalitis virus (JEV) infection through the activation of neighboring pericytes. We found that cultured brain pericytes were susceptible to JEV infection but were without signs of remarkable cytotoxicity. JEV-infected pericytes were found to release biologically active molecules which activated ubiquitin proteasome, degraded zonula occludens-1 (ZO-1), and disrupted endothelial barrier integrity in cultured brain microvascular endothelial cells. Infection of pericytes with JEV was found to elicit elevated production of interleukin-6 (IL-6), which contributed to the aforementioned endothelial changes. We further demonstrated that ubiquitin-protein ligase E3 component n-recognin-1 (Ubr 1) was a key upstream regulator which caused proteasomal degradation of ZO-1 downstream of IL-6 signaling. During JEV central nervous system trafficking, endothelial cells rather than pericytes are directly exposed to cell-free viruses in the peripheral bloodstream. Therefore, the results of this study suggest that subsequent to primary infection of endothelial cells, JEV infection of pericytes might contribute to the initiation and/or augmentation of Japanese encephalitis-associated BBB breakdown in concerted action with other unidentified barrier disrupting factors.

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Section: Discussionmentioning

confidence: 99%

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Chen

et al. 2014

J Virol

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“…Recently, Itch was shown to ubiquitinate and regulate the expression of angiomotin (AMOT). AMOT family members are involved in angiogenesis, integrity of tight junctions, formation of lamellipodia, migration, and epithelial-mesenchymal transition (EMT) (33). The interaction of LMP2A with Itch may affect the formation and integrity of tight junctions and promote wound healing migration.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein-2A Induces ITAM/Syk- and Akt-Dependent Epithelial Migration through αV-Integrin Membrane Translocation

Fotheringham

Coalson

Raab‐Traub

2012

J Virol

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Epstein-Barr virus (EBV) is a highly prevalent herpesvirus associated with epithelial cancers, including nasopharyngeal carcinoma (NPC). The EBV protein latent membrane protein 2 (LMP2) is expressed in NPC tumor tissue and has been shown to induce transformation, inhibit differentiation, and promote migration of epithelial cells. In this study, the effect of LMP2A on migration of human epithelial cells was further analyzed. LMP2A expression induced migration in human foreskin keratinocytes (HFK) and HaCaT keratinocytes measured by wound healing scratch assay and chemoattractant-induced Transwell migration assay. The induction of migration by LMP2A required the ITAM signaling domain of LMP2A and activation of the Syk tyrosine kinase. LMP2A-induced Transwell migration required the Akt signaling pathway, and activation of Akt by LMP2A required the ITAM signaling domain of LMP2A. LMP2A also induced phosphorylation of the Akt target GSK3β, a Wnt signaling mediator that has been shown to regulate the activity of focal adhesion kinase (FAK), a tyrosine kinase activated by clustering and ligand interaction of integrins. Inhibition of either FAK or its signaling mediator Src kinase inhibited LMP2A-induced migration. Interestingly, αV-integrin was greatly increased in membrane-enriched fractions by LMP2A, and a neutralizing antibody to αV-integrin blocked migration, suggesting that the effects of LMP2A on membrane-localized αV-integrin promoted migration. The results of this study indicate that LMP2A expression in human epithelial cells induces αV-integrin-dependent migration through a mechanism requiring ITAM-mediated Syk and Akt activation and inducing membrane translocation or stabilization of αV-integrin and FAK activation. The specific effects of LMP2A on an integrin with a diverse repertoire of ligand specificities could promote migration of different cell types and be initiated by multiple chemoattractants.

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“…Amotl2 is one of the three members of the Motin family of proteins that also include angiomotin (Amot) and Angiomotinlike1 (Amotl1) (Bratt et al, 2002), all of which regulate cytoskeletal organization (Ernkvist et al, 2009;Huang et al, 2007;Wang et al, 2011b). Amotl2 also serves as a scaffold for polarity and signaling proteins in migrating endothelial cells and at tight junctions of epithelial cells (Ernkvist et al, 2009;Li et al, 2012;Paramasivam et al, 2011;Wang et al, 2012;Zhao et al, 2011). Flii, a homolog of the Drosophila Flightless gene (Miklos and De Couet, 1990), is a member of the gelsolin family of actin organizing proteins, which control the balance between stable adhesion and migration during wound healing (Adams et al, 2009;Archer et al, 2004;Cowin et al, 2007;Kopecki and Cowin, 2008;Kopecki et al, 2011).…”

Section: Identification Of Ll5b-interacting Proteinsmentioning

confidence: 99%

“…Second, we analyzed the role of one novel interactor, Amotl2, in podosome structure and postsynaptic maturation. Amotl2 is a member of the Motin family (Bratt et al, 2002) that regulates cytoskeletal organization and also serves as a scaffold for polarity organizing proteins in migrating endothelial cells and for signaling molecules in epithelial cells (Ernkvist et al, 2009;Huang et al, 2007;Li et al, 2012;Paramasivam et al, 2011;Wang et al, 2012;Wang et al, 2011b;Zhao et al, 2011). RNAimediated depletion of Amotl2 led to enlargement of synaptic podosomes and a precisely corresponding alteration in the topology of AChR aggregates.…”

Section: Introductionmentioning

confidence: 99%

Amotl2 interacts with LL5β, localizes to podosomes and regulates postsynaptic differentiation in muscle

Prószyński

Sanes²

2013

Journal of Cell Science

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SummaryNeuromuscular junctions (NMJs) in mammalian skeletal muscle undergo a postnatal topological transformation from a simple oval plaque to a complex branched structure. We previously showed that podosomes, actin-rich adhesive organelles, promote the remodeling process, and demonstrated a key role for one podosome component, LL5b. To further investigate molecular mechanisms of postsynaptic maturation, we purified LL5b-associated proteins from myotubes and showed that three regulators of the actin cytoskeleton -Amotl2, Asef2 and Flii -interact with LL5b. These and other LL5b-interacting proteins are associated with conventional podosomes in macrophages and podosome-like invadopodia in fibroblasts, strengthening the close relationship between synaptic and non-synaptic podosomes. We then focused on Amotl2, showing that it is associated with synaptic podosomes in cultured myotubes and with NMJs in vivo. Depletion of Amotl2 in myotubes leads to increased size of synaptic podosomes and corresponding alterations in postsynaptic topology. Depletion of Amotl2 from fibroblasts disrupts invadopodia in these cells. These results demonstrate a role for Amotl2 in synaptic maturation and support the involvement of podosomes in this process.

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The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation

Cited by 68 publications

References 22 publications

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Epstein-Barr Virus Latent Membrane Protein-2A Induces ITAM/Syk- and Akt-Dependent Epithelial Migration through αV-Integrin Membrane Translocation

Amotl2 interacts with LL5β, localizes to podosomes and regulates postsynaptic differentiation in muscle

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