The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination

Choi, Kyu Sung; Choi, Hyun Jung; Lee, Jin Kyu; Im, Suhjean; Zhang, Haiying; Jeong, Yoonjeong; Park, Jeong Ae; Lee, In Kyu; Kim, Young Myeong; Kwon, Young Guen

doi:10.1016/j.cellsig.2016.07.015

Cited by 39 publications

(43 citation statements)

References 49 publications

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“…HECW1 interacts with RNF43 to enhance pro-apoptotic activity through p53 (39). HECW2 enhances endothelial cell-to-cell junctions, and its deficiency impairs angiogenesis (40). This suggested that HSF1 may interact with different members of the E3 ubiquitin protein ligase family under pathological and normal conditions.…”

Section: Hsf1 May Have Unique Phosphorylation In Sccmentioning

confidence: 99%

Proteomics analysis of proteins interacting with heat shock factor 1 in squamous cell carcinoma of the cervix

Zhang

et al. 2019

Oncol Lett

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Protein interactions are crucial for maintaining homeostasis. Heat shock factor 1 (HSF1), a transcription factor that interacts with various proteins, is highly expressed in squamous cell carcinoma (SCC) of the cervix. The aim of the present study was to investigate the protein interaction profile of HSF1 in cervical SCC. Proteins interacting with HSF1 in SCC tissue and non-cancerous control (Ctrl) tissue were obtained by immunoprecipitation, separated by SDS-PAGE, identified by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry and analyzed using bioinformatics methods. A total of 220 and 241 proteins were identified by mass spectrometry in the tissues of Ctrl and SCC samples, respectively, among which 172 were detected exclusively in SCC (Pro-S), 151 exclusively in Ctrl (Pro-C) and 69 in both groups (Pro-B). The protein interaction profiles were different in each group; the STRING database identified three proteins that interacted with HSF1 directly, including insulin-like growth factor 1 receptor and small nuclear RNA-activating protein complex subunit 4 in Pro-C and small ubiquitin-related modifier 1 in Pro-S. Functional enrichment analysis of Gene Ontology revealed that the top terms were alternative splicing in Pro-S and polymorphism in Pro-C. In Pro-S, more categories were related to protein modification, such as phosphorylation, ubiquitination and acetylation. Therefore, HSF1 may influence the occurrence and development of cervical SCC by interacting with specific proteins.Abbreviations: HSF1, heat shock factor 1; IP, immunoprecipitation; MS, mass spectrometry; SCC, squamous cell carcinoma of cervix Key words: heat shock factor 1, protein interaction, squamous cell carcinoma of cervix, immunoprecipitation, mass spectrometry

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Section: Hsf1 May Have Unique Phosphorylation In Sccmentioning

confidence: 99%

Proteomics analysis of proteins interacting with heat shock factor 1 in squamous cell carcinoma of the cervix

Zhang

et al. 2019

Oncol Lett

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“…So next we tested whether TRIM16 affects ubiquitination status of NRF2. The K48‐linked poly‐ubiquitination of a protein is known to target it for proteasomal degradation and the K63‐linked poly‐ubiquitination is important for varied functions including protein trafficking, proteins oligomerization, protein stability, and activation of signaling pathways (Jiang et al , ; Nazio et al , ; Erpapazoglou et al , ; Choi et al , ). To determine how TRIM16 affects NRF2 ubiquitination, we performed immunoprecipitation assays in the presence of two different variants of ubiquitin proteins, one that can only be ubiquitinated at lysine 48 residue (HA‐K48‐UB) and other that can only be ubiquitinated at lysine 63 residue (HA‐K63‐UB).…”

Section: Resultsmentioning

confidence: 99%

TRIM16 controls assembly and degradation of protein aggregates by modulating the p62‐NRF2 axis and autophagy

et al. 2018

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Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress‐induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62‐NRF2 axis. We show that TRIM16 is an integral part of the p62‐KEAP1‐NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2. Under oxidative and proteotoxic stress conditions, TRIM16 activates ubiquitin pathway genes and p62 via NRF2, leading to ubiquitination of misfolded proteins and formation of protein aggregates. We further show that TRIM16 acts as a scaffold protein and, by interacting with p62, ULK1, ATG16L1, and LC3B, facilitates autophagic degradation of protein aggregates. Thus, TRIM16 streamlines the process of stress‐induced aggregate clearance and protects cells against oxidative/proteotoxic stress‐induced toxicity in vitro and in vivo. Taken together, this work identifies a new mechanism of protein aggregate turnover, which could be relevant in protein aggregation‐associated diseases such as neurodegeneration.

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“…115 AMOTL1, a component of tight junctions, regulates endothelial cell junctional structure, permeability, polarity, migration, capillary formation, and vascular stability. Similarly to the regulation of p73 activity, binding of HECW2 with AMOTL1 promotes AMOTL1 K63-ubiquitination and increases stability in endothelial cells, while the loss of AMOTL1 promotes angiogenic sprouting 116 (Figure 7B).…”

Section: Hecw2 Binds P73 and Amotl1mentioning

confidence: 94%

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

2020

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The ubiquitin‐proteasome system (UPS) governs the protein degradation process and balances proteostasis and cellular homeostasis. It is a well‐controlled mechanism, in which removal of the damaged or excessive proteins is essential in driving signal pathways for cell survival or death. Accumulation of damaged proteins and failure in removal may contribute to disease initiation such as in cancers and neurodegenerative diseases. In this notion, specific protein‐protein interaction is essential for the recognition of targeted proteins in UPS. WW domain plays an indispensable role in the protein‐protein interactions during signaling. Among the 51 WW domain‐containing proteins in the human proteomics, near one‐quarter of them are involved in the UPS, suggesting that WW domains are crucial modules for driving the protein‐protein binding and subsequent ubiquitination and degradation. In this review, we detail a broad spectrum of WW domains in protein‐protein recognition, signal transduction, and relevance to diseases. New perspectives in dissecting the molecular interactions are provided.

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The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination

Cited by 39 publications

References 49 publications

Proteomics analysis of proteins interacting with heat shock factor 1 in squamous cell carcinoma of the cervix

Proteomics analysis of proteins interacting with heat shock factor 1 in squamous cell carcinoma of the cervix

TRIM16 controls assembly and degradation of protein aggregates by modulating the p62‐NRF2 axis and autophagy

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

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