A Small Organic Molecule Blocks EGFR Transport into the Nucleus by the Nonclassical Pathway Resulting in Repression of Cancer Invasion

Ha, Siyoung; Jeong, Jangho; Oh, Joosung; Rhee, Sangmyung; Ham, Seung Wook

doi:10.1002/cbic.201700489

Cited by 7 publications

(10 citation statements)

References 39 publications

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“…It has been reported that EGFR is transported into the nucleus by forming a complex with the nuclear transport proteins karyopherin alpha/karyopherin subunit beta 1 (KPNA/KPNB1) in the classical transport pathway or with KPNB1 alone through the nonclassical transport pathway. , Recently, we have shown that ligand-activated EGFR is translocated into the nucleus by forming a complex with KPNB1, but not with KPNA/KPNB1, supporting the nonclassical transport pathway . We also found that a small organic molecule with a strong antiproliferative effect against several cancer cells binds strongly to KPNB1 and blocks the nuclear transport of EGF-activated EGFR . As a result, the transcriptional target proteins of nEGFR are downregulated in cells treated with KPNB1 inhibitor.…”

supporting

confidence: 60%

Transport Mechanism for Nuclear Localization of Irradiation-Activated EGFR Measured by Single-Molecule Pull-Down Assay

Jang

Koh

et al. 2023

Biochemistry

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Nuclear transport of epidermal growth factor receptor (EGFR) is considered to be a key cause of radiation resistance in cancer therapy. Here, we showed that irradiation-activated EGFR binds to the nuclear transport protein karyopherin alpha (KPNA) rather than karyopherin subunit beta 1 (KPNB1), through a single-molecule pull-down assay, which allows measurement of the binding affinity by single proteins in cell lysate without an additional purification step. We also obtained kinetic parameters for the binding between the phosphorylated nuclear localization signal (NLS) peptide of EGFR ( 645 RRRHIVRKRpTLRR 657 ) and KPNA. This observation may help developing small molecules to modulate nuclear transport, which potentially reduces the radiation resistance during irradiation therapy.

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supporting

confidence: 60%

Transport Mechanism for Nuclear Localization of Irradiation-Activated EGFR Measured by Single-Molecule Pull-Down Assay

Jang

Koh

et al. 2023

Biochemistry

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“…Several inhibitors of nuclear import and export have been developed as anti-cancer therapeutic strategy (Bi et al 2005; Parikh et al 2014; Mahipal and Malafa, 2016; Ha et al 2017), with at least two (Selinexor and SL-801) currently being in human clinical trials (NIH, 2017). Basic discovery research over the last two decades has shown that disruption of nuclear transport is a key aspect of several medically important cancers (Mahipal and Malafa, 2016).…”

Section: Nuclear Transport As a Therapeutic Targetmentioning

confidence: 99%

Nuclear transport inEntamoeba histolytica: knowledge gap and therapeutic potential

Gwairgi

Ghildyal

2018

Parasitology

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Entamoeba histolytica is the protozoan parasite that causes human amoebiasis. It is one of the leading parasitic disease burdens in tropical regions and developing countries, with spread to developed countries through migrants from and travellers to endemic regions.Understanding E. histolytica's invasion mechanisms requires an understanding of how it interacts with external cell components and how it engulfs and kills cells (phagocytosis). Recent research suggests that optimal phagocytosis requires signalling events from the cell surface to the nucleus via the cytoplasm, and the induction of several factors that are transported to the plasma membrane. Current research in other protozoans suggests the presence of proteins with nuclear localization signals, nuclear export signals and Ran proteins; however, there is limited literature on their functionality and their functional similarity to higher eukaryotes.Based on learnings from the development of antivirals, nuclear transport elements in E. histolytica may present viable, specific, therapeutic targets.In this review, we aim to summarize our limited knowledge of the eukaryotic nuclear transport mechanisms that are conserved and may function in E. histolytica.

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“…Karyopherin β1 (KPNB1) is a major nuclear importer of the karyopherin family and has been reported to regulate diverse cellular process, such as apoptosis [ 7 ], proliferation [ 8 ], and invasion [ 9 ]. Many researchers have demonstrated the important role of KPNB1 in cancer development.…”

Section: Introductionmentioning

confidence: 99%

Tumor-promoting properties of karyopherin β1 in melanoma by stabilizing Ras-GTPase-activating protein SH3 domain-binding protein 1

Yang

et al. 2022

Cancer Gene Ther

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The nuclear import receptor karyopherin β1 (KPNB1), a member of the Karyopherin protein family, is reported to be overexpressed in various cancers and promote carcinogenesis. By analyzing the correlation between the expression of KPNB1 and the overall survival rate of melanoma patients, we found that melanoma patients with higher expression of KPNB1 had worse survival. Furthermore, the database analyzed that the KPNB1 mRNA level was higher in melanoma samples than that in skin nevus tissues. We thus proposed that KPNB1 played a role in promoting melanoma development, and conducted gain-of- and loss-of-function experiments to test our hypothesis. We found that KPNB1 knockdown significantly retarded the growth and metastasis of melanoma cells in vitro and in vivo, and increased their sensitivity towards the anti-tumor drug cisplatin. KPNB1 overexpression had opposite effects. Notably, in melanoma cells, KPNB1 overexpression significantly decreased Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) protein level, which was also overexpressed in melanoma samples and enhanced malignant behaviors of melanoma cells. We further demonstrated that KPNB1 overexpression induced deubiquitination of G3BP1, and prevented its degradation. However, KPNB1 overexpression hardly affected the nuclear translocation of G3BP1. Additionally, alterations induced by KPNB1 overexpression were partly reversed by G3BP1 inhibition. Therefore, the results suggest that KPNB1 may promote melanoma progression by stabilizing the G3BP1 protein. KPNB1-G3BP1 axis represents a potential therapeutic targetable node for melanoma.

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A Small Organic Molecule Blocks EGFR Transport into the Nucleus by the Nonclassical Pathway Resulting in Repression of Cancer Invasion

Cited by 7 publications

References 39 publications

Transport Mechanism for Nuclear Localization of Irradiation-Activated EGFR Measured by Single-Molecule Pull-Down Assay

Transport Mechanism for Nuclear Localization of Irradiation-Activated EGFR Measured by Single-Molecule Pull-Down Assay

Nuclear transport inEntamoeba histolytica: knowledge gap and therapeutic potential

Tumor-promoting properties of karyopherin β1 in melanoma by stabilizing Ras-GTPase-activating protein SH3 domain-binding protein 1

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