FASEB JOURNAL
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2019
·Vol. 33
·期 5
·6311-6326
·
IF 5.391
Yifan Wang,Xiaolong Zhang,Jilai Tian,Jinjun Shan,Yunfeng Hu,Yiqian Zhai,Jun Guo
Neuronal polarization depends on the interaction of intracellular chemical and mechanical activities in which the cytoplasmic protein, talin, plays a pivotal role during neurite growth. To better understand the mechanism underlying talin function in neuronal polarization, we overexpressed several truncated forms of talin and found that the presence of the rod domain within the overexpressed talin is required for its positive effect on neurite elongation because the neurite number only increased when the talin head region was overexpressed. The tension in the talin rod was recognized using a Förster resonance energy transfer-based tension probe. Nerve growth factor treatment resulted in inward tension of talin elicited by microfilament force and outward osmotic pressure. By contrast, the glial scar-inhibitor aggrecan weakened these forces, suggesting that interactions between inward pull forces in the talin rod and outward osmotic pressure participate in neuronal polarization. Integrin activation is also involved in up-regulation of talin tension and osmotic pressure. Aggrecan stimuli resulted in up-regulation of docking protein 1 (DOK1), leading to the down-regulation of integrin activity and attenuation of the intracellular mechanical force. Our study suggests interactions between the intracellular inward tension in talin and the outward osmotic pressure as the effective channel for promoting neurite outgrowth, which can be up-regulated by integrin activation and down-regulated by DOK1.—Wang, Y., Zhang, X., Tian, J., Shan, J., Hu, Y., Zhai, Y., Guo, J. Talin promotes integrin activation accompanied by generation of tension in talin and an increase in osmotic pressure in neurite outgrowth. FASEB J. 33, 6311–6326 (2019). www.fasebj.org
研究领域:
神经科学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Cancer
·
2020
·
IF 3.565
Ying Song,Chen Li,Yahan Fu,Qiu Xie,Jun Guo,Guangming Li,Huiwen Wu
The integrin receptor protein talin plays vital roles in intracellular chemical and mechanical activities, and it is implicated in the high invasion and poor prognosis of non-small cell lung cancer (NSCLC). To better understand the mechanism underlying the function of talin in NSCLC invasion and metastasis, a few newly designed tension probe based on Förster resonance energy transfer was used for real-time observation of tension changes in A549 cells. High NSCLC cell aggressiveness was found to be accompanied with inward talin and outward glial fibrillary acidic protein (GFAP) tensions, which are closely associated with microfilament (MF) force and intracellular osmotic potential. The increased osmotic pressure resulted from the production of intracellular protein nanoparticles and the related ion influx. Furthermore, integrin activation was found to adjust the talin and GFAP tensions. Disruption of the interaction between talin and MFs blocked the mechanical source of talin, reducing both talin tension and osmotic pressure and thus inhibiting NSCLC cell invasion and migration. Consequently, our study demonstrates that talin is involved in NSCLC invasion and migration via its inward tension and that the integrin pathway is correlated closely with protein-nanoparticle-induced outward osmotic pressure.
研究领域:
癌症生物学
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细胞生物学
·
分子生物学
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生物物理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FEBS Journal
·
2024
·
IF 5.5
Ling Wang,Shibo Sun,Haowen Liu,Qiuyu Zhang,Yao Meng,Fan Sun,Jianjun Zhang,Haiyan Liu,Weiping Xu,Zhiwei Ye,Jie Zhang,Bingbing Sun,Jianqiang Xu
Thioredoxin reductase 1 (TXNRD1) has been identified as one of the promising chemotherapeutic targets in cancer cells. Therefore, a novel TXNRD1 inhibitor could accelerate chemotherapy in clinical anticancer research. In this study, glaucocalyxin A (GlauA), a natural diterpene extracted from Rabdosia japonica var. glaucocalyx , was identified as a novel inhibitor of TXNRD1. We found that GlauA effectively inhibited recombinant TXNRD1 and reduced its activity in gastric cancer cells without affecting the enzyme's expression level. Mechanistically, the selenocysteine residue (U498) of TXNRD1 was irreversibly modified by GlauA through a Michael addition. Additionally, GlauA formed a covalent adduct with glutathione (GSH) and disrupted cellular redox balance by depleting cellular GSH. The inhibition of TXNRD1 and depletion of GSH by GlauA conferred its cytotoxic effects in spheroid culture and Transwell assays in AGS cells. The disulfide stress induced cytotoxicity of GlauA could be mitigated by adding reducing agents, such as DTT and β-ME. Furthermore, the FDA-approval drug auranofin, a TXNRD1 inhibitor, triggered oligomerization of the cytoskeletal protein Talin-1 in AGS cells, indicating that inhibiting TXNRD1 triggered disulfide stress. In conclusion, this study uncovered GlauA as an efficient inhibitor of TXNRD1 and demonstrated the potential of TXNRD1 inhibition as an effective anticancer strategy by disrupting redox homeostasis and inducing disulfide stress.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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