Liquid–liquid phase separation drives the β‐catenin destruction complex formation

Shi, Qiaoni; Kang, Kexin; Chen, Ye-Guang

doi:10.1002/bies.202100138

Cited by 8 publications

(8 citation statements)

References 81 publications

(159 reference statements)

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“…Recent studies have demonstrated that AXIN and APC undergo LLPS, which is critical for their function in inhibiting the Wnt/β-catenin pathway. 187 , 188 Hyperactivation of the Wnt pathway caused by APC mutations is prevalent in a large portion of human CRCs, and these mutants play a pivotal role in the initiation of tumorigenesis by influencing cell differentiation and facilitating rapid proliferation. 189 , 190 The above-described examples strongly demonstrate that the regulation of Wnt signaling pathway hyperactivation can be performed in two directions: inhibiting the phase separation induced by Wnt signaling or promoting the LLPS of the destruction complex.…”

Section: Aberrant Llps In Cancermentioning

confidence: 99%

Liquid–liquid phase separation in tumor biology

Tong

Tang

et al. 2022

Sig Transduct Target Ther

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Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins and nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response and repair, transcription, and signal transduction. Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer, and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology. In this review, we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS. In addition, we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.

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Section: Aberrant Llps In Cancermentioning

confidence: 99%

Liquid–liquid phase separation in tumor biology

Tong

Tang

et al. 2022

Sig Transduct Target Ther

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“…Following recruitment to the destruction complex, β-catenin is phosphorylated, ubiquitylated, and then degraded by the proteasome. Recently, it has been shown that the destruction complex is organized via liquid–liquid phase separation (LLPS) of Axin ( Li et al, 2020 ; Nong et al, 2021 ; Shi et al, 2021 ). Upon binding of Wnt ligands to the cell surface, Frizzled (Fzd) receptor and low-density-lipoprotein-related protein 5/6 (LRP5/6) coreceptor, cytosolic Dishevelled (Dvl) is recruited to the PM via its interaction with Fzd ( Cliffe et al, 2003 ) and provides a docking site for Axin ( Cliffe et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Dishevelled phase separation promotes Wnt signalosome assembly and destruction complex disassembly

Kang

Shi

Wang³

et al. 2022

Journal of Cell Biology

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The amplitude of Wnt/β-catenin signaling is precisely controlled by the assembly of the cell surface–localized Wnt receptor signalosome and the cytosolic β-catenin destruction complex. How these two distinct complexes are coordinately controlled remains largely unknown. Here, we demonstrated that the signalosome scaffold protein Dishevelled 2 (Dvl2) undergoes liquid–liquid phase separation (LLPS). Dvl2 LLPS is mediated by an intrinsically disordered region and facilitated by components of the signalosome, such as the receptor Fzd5. Assembly of the signalosome is initiated by rapid recruitment of Dvl2 to the membrane, followed by slow and dynamic recruitment of Axin1. Axin LLPS mediates assembly of the β-catenin destruction complex, and Dvl2 attenuates LLPS of Axin. Compared with the destruction complex, Axin partitions into the signalosome at a lower concentration and exhibits a higher mobility. Together, our results revealed that Dvl2 LLPS is crucial for controlling the assembly of the Wnt receptor signalosome and disruption of the phase-separated β-catenin destruction complex.

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“…Recent studies have shown that LLPS can occur in some signaling molecules in Wnt signaling pathway, which is very important for the regulation of Wnt functions 133 . IDR in Axin can drive its phase separation and promote the formation of destruction complex.…”

Section: The Role Of Llps In Oncogenic Signalingmentioning

confidence: 99%

“…Phase separation phenomenon has also been found in APC molecules, which can enhance the dynamic of Axin phase separation droplets in vitro. The assembly of β-catenin destruction complex and β-catenin phosphorylation by GSK3β/CK1α are driven by phase separation, which then maintain β-catenin protein stability and regulate Wnt/β-catenin signal transduction 133 . In vitro, IDRs of APC undergoes phase separation.…”

Section: The Role Of Llps In Oncogenic Signalingmentioning

confidence: 99%

“…Dvl was also observed to form puncta in cells, and its DIX domain is important for the puncta formation. Although Dvl protein has been proposed to have an ability to undergo LLPS, there is no experimental evidence that has been reported by far 133 , 135 , 136 . Recent studies have shown that coactivator, mediators and some transcription factors enrich on super enhancers to form phase separation condensates 110 , 137 .…”

Section: The Role Of Llps In Oncogenic Signalingmentioning

confidence: 99%

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Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

Qiu¹,

Tan²,

Xia³

et al. 2022

Int. J. Biol. Sci.

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Cancer is a public health problem of great concern, and it is also one of the main causes of death in the world. Cancer is a disease characterized by dysregulation of diverse cellular processes, including avoiding growth inhibitory factors, avoiding immune damage and promoting metastasis, etc. However, the precise mechanism of tumorigenesis and tumor progression still needs to be further elucidated. Formations of liquid-liquid phase separation (LLPS) condensates are a common strategy for cells to achieve diverse functions, such as chromatin organization, signal transduction, DNA repair and transcriptional regulation, etc. The biomolecular aggregates formed by LLPS are mainly driven by multivalent weak interactions mediated by intrinsic disordered regions (IDRs) in proteins. In recent years, aberrant phase separations and transition have been reported to be related to the process of various diseases, such as neurodegenerative diseases and cancer. Herein, we discussed recent findings that phase separation regulates tumor-related signaling pathways and thus contributes to tumor progression. We also reviewed some tumor virus-associated proteins to regulate the development of virus-associated tumors via phase separation. Finally, we discussed some possible strategies for treating tumors by targeting phase separation.

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Liquid–liquid phase separation drives the β‐catenin destruction complex formation

Cited by 8 publications

References 81 publications

Liquid–liquid phase separation in tumor biology

Liquid–liquid phase separation in tumor biology

Dishevelled phase separation promotes Wnt signalosome assembly and destruction complex disassembly

Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

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