Cullin3/<scp>KCTD</scp>5 induces monoubiquitination of ΔNp63α and impairs its activity

He, Huawei; Peng, Yougong; Fan, Shijie; Chen, Yonglong; Zheng, Xuan; Li, Chenghua

doi:10.1002/1873-3468.13104

Cited by 9 publications

(10 citation statements)

References 27 publications

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“…Previous studies demonstrated that KCTD5 interacts with Cullin3, an E3 ligase that participates in the process of ubiquitination 15,16,55 . This interaction promotes poly‐ 16 and mono‐ubiquitination 56 of several proteins. Ubiquitination is a well‐known negative regulatory mechanism for membrane stability of ion channels, by affecting endocytosis and degradation of these proteins 57‐61 .…”

Section: Discussionmentioning

confidence: 96%

KCTD5, a novel TRPM4‐regulatory protein required for cell migration as a new predictor for breast cancer prognosis

et al. 2020

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Transient receptor potential melastatin 4 (TRPM4) is a Ca2+‐activated nonselective cationic channel that regulates cell migration and contractility. Increased TRPM4 expression has been related to pathologies, in which cytoskeletal rearrangement and cell migration are altered, such as metastatic cancer. Here, we identify the K+ channel tetramerization domain 5 (KCTD5) protein, a putative adaptor of cullin3 E3 ubiquitin ligase, as a novel TRPM4‐interacting protein. We demonstrate that KCTD5 is a positive regulator of TRPM4 activity by enhancing its Ca2+ sensitivity. We show that through its effects on TRPM4 that KCTD5 promotes cell migration and contractility. Finally, we observed that both TRPM4 and KCTD5 expression are increased in distinct patterns in different classes of breast cancer tumor samples. Together, these data support that TRPM4 activity can be regulated through expression levels of either TRPM4 or KCTD5, not only contributing to increased understanding of the molecular mechanisms involved on the regulation of these important ion channels, but also providing information that could inform treatments based on targeting these distinct molecules that define TRPM4 activity.

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Section: Discussionmentioning

confidence: 96%

KCTD5, a novel TRPM4‐regulatory protein required for cell migration as a new predictor for breast cancer prognosis

et al. 2020

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“…Cdc20–APC/C is important for degradation during mitosis and Cdh1–APC/C during differentiation, and the E3‐ligase TRIM8 also destabilises ΔNp63α [227]. Metformin downregulation of ΔNp63 was linked to increased ubiquitination [228], whilst mono‐ubiquitination by cullin3/KCTD5 inhibited activity without causing degradation [229]. On the other side, Stxbp4 inhibits APC/C‐mediated degradation and maintains ΔNp63 levels in SCC [226,230], as does the deubiquitylase USP28 [231].…”

Section: Post‐translational Modifications That Influence P63 Protein Stability And/or Activitymentioning

confidence: 99%

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post‐transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post‐transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell‐context and cell–matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…KCTD5 is the first member of the KCTD family whose tridimensional structure has been described [ 33 ]. Furthermore, its interaction with Cul3 has been extensively studied [ 23 , 34 , 35 , 36 , 37 ]. KCTD5 participates in such uneven processes as anti-proliferative response, Helicobacter pylori adherence to gastric cells and sleep regulation [ 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, its interaction with Cul3 has been extensively studied [ 23 , 34 , 35 , 36 , 37 ]. KCTD5 participates in such uneven processes as anti-proliferative response, Helicobacter pylori adherence to gastric cells and sleep regulation [ 37 , 38 , 39 ]. Interestingly, KCTD5 precludes the activation of the known pro-migratory and pro-carcinogenic AKT pathway by switch-off the G-protein coupled receptors (GPCR) signaling through the Gβγ subunit proteasomal degradation [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

K+ Channel Tetramerization Domain 5 (KCTD5) Protein Regulates Cell Migration, Focal Adhesion Dynamics and Spreading through Modulation of Ca2+ Signaling and Rac1 Activity

Canales

Cruz

Díaz

et al. 2020

Cells

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Cell migration is critical for several physiological and pathophysiological processes. It depends on the coordinated action of kinases, phosphatases, Rho-GTPases proteins, and Ca2+ signaling. Interestingly, ubiquitination events have emerged as regulatory elements of migration. Thus, the role of proteins involved in ubiquitination processes could be relevant to a complete understanding of pro-migratory mechanisms. KCTD5 is a member of Potassium Channel Tetramerization Domain (KCTD) proteins that have been proposed as a putative adaptor for Cullin3-E3 ubiquitin ligase and a novel regulatory protein of TRPM4 channels. Here, we study whether KCTD5 participates in cell migration-associated mechanisms, such as focal adhesion dynamics and cellular spreading. Our results show that KCTD5 CRISPR/Cas9- and shRNA-based depletion in B16-F10 cells promoted an increase in cell migration and cell spreading, and a decrease in the focal adhesion area, consistent with an increased focal adhesion disassembly rate. The expression of a dominant-negative mutant of Rho-GTPases Rac1 precluded the KCTD5 depletion-induced increase in cell spreading. Additionally, KCTD5 silencing decreased the serum-induced Ca2+ response, and the reversion of this with ionomycin abolished the KCTD5 knockdown-induced decrease in focal adhesion size. Together, these data suggest that KCTD5 acts as a regulator of cell migration by modulating cell spreading and focal adhesion dynamics through Rac1 activity and Ca2+ signaling, respectively.

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Cullin3/KCTD5 induces monoubiquitination of ΔNp63α and impairs its activity

Cited by 9 publications

References 27 publications

KCTD5, a novel TRPM4‐regulatory protein required for cell migration as a new predictor for breast cancer prognosis

KCTD5, a novel TRPM4‐regulatory protein required for cell migration as a new predictor for breast cancer prognosis

The foggy world(s) of p63 isoform regulation in normal cells and cancer

K+ Channel Tetramerization Domain 5 (KCTD5) Protein Regulates Cell Migration, Focal Adhesion Dynamics and Spreading through Modulation of Ca2+ Signaling and Rac1 Activity

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