Cell Research最新文献_第3页

Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1 溶酶体表皮生长因子受体作为独立于其激酶活性的 Rheb-GEF 激活 mTORC1

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01110-x

Xiaobo He, Qiu-Xia Wang, Denghui Wei, Yujie Lin, Xia Zhang, Yuanzhong Wu, Xuexia Qian, Zhihao Lin, Beibei Xiao, Qinxue Wu, Zhen Wang, Fengtao Zhou, Zhihao Wei, Jingxuan Wang, Run Gong, Ruhua Zhang, Qingling Zhang, Ke Ding, Song Gao, Tiebang Kang

{"title":"Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1","authors":"Xiaobo He, Qiu-Xia Wang, Denghui Wei, Yujie Lin, Xia Zhang, Yuanzhong Wu, Xuexia Qian, Zhihao Lin, Beibei Xiao, Qinxue Wu, Zhen Wang, Fengtao Zhou, Zhihao Wei, Jingxuan Wang, Run Gong, Ruhua Zhang, Qingling Zhang, Ke Ding, Song Gao, Tiebang Kang","doi":"10.1038/s41422-025-01110-x","DOIUrl":"https://doi.org/10.1038/s41422-025-01110-x","url":null,"abstract":"Oncogenic mutations in EGFR often result in EGF-independent constitutive activation and aberrant trafficking and are associated with several human malignancies, including non-small cell lung cancer. A major consequence of EGFR mutations is the activation of the mechanistic target of rapamycin complex 1 (mTORC1), which requires EGFR kinase activity and downstream PI3K/AKT signaling, resulting in increased cell proliferation. However, recent studies have elucidated kinase-independent roles of EGFR in cell survival and cancer progression. Here, we report a cis mTORC1 activation function of EGFR that is independent of its kinase activity. Our results reveal that lysosomal localization of EGFR is critical to mTORC1 activation, where EGFR physically binds Rheb, acting as a guanine exchange factor (GEF) for Rheb, with its Glu804 serving as a potential glutamic finger. Genetic knock-in of EGFR-E804K in cells reduces the level of GTP-bound Rheb, and significantly suppresses mTORC1 activation, cell proliferation and tumor growth. Different tyrosine kinase inhibitors exhibit distinct effects on EGFR-induced mTORC1 activation, with afatinib, which additionally blocks EGFR’s GEF activity, causing a much greater suppression of mTORC1 activation and cell growth, and erlotinib, which targets only kinase activity, resulting in only a slight decrease. Moreover, a novel small molecule, BIEGi-1, was designed to target both the Rheb-GEF and kinase activities of EGFR, and shows a strong inhibitory effect on the viability of cells harboring EGFR mutants. These findings unveil a fundamental event in cell growth and suggest a promising strategy against cancers with EGFR mutations.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"47 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding NLRP3: Phase separation enters the scene 解码NLRP3：相位分离进入场景

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01120-9

Niklas A. Schmacke, Veit Hornung

引用次数: 0

Gasdermin D pores hitch a ride: extracellular vesicles spread pyroptosis 气真皮蛋白D毛孔搭便车：细胞外囊泡扩散热亡

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01109-4

Gang Du, Hao Wu

引用次数: 0

Orchestrating NTSR1 signaling from the interface 编排来自接口的NTSR1信令

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01121-8

Xianglin Huang, Brian E. Krumm, Bryan L. Roth

引用次数: 0

Spliceosome-associated quality control 剪接体相关质量控制

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01118-3

Nikita Sharaev, Jiangfeng Zhao, Wojciech P. Galej

引用次数: 0

Pyrimidine synthase CAD deamidates and inactivates p53. 嘧啶合酶CAD使p53脱酰胺并失活。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-04-17 DOI: 10.1038/s41422-025-01112-9

Yue Qi, Zizheng Tan, Hanyu Chen, Ziqi Xiao, Liang Zhang, Boxuan Wu, Chennan Liu, Yunqian Gao, Xueyan Yang, Lingqian Wu, Lei Lu, Hongyan Wang

引用次数: 0

Author Correction: Structural and functional evidence that GPR30 is not a direct estrogen receptor. 作者更正：结构和功能证据表明GPR30不是直接雌激素受体。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-04-16 DOI: 10.1038/s41422-025-01113-8

Heng Liu, Shimeng Guo, Antao Dai, Peiyu Xu, Xin Li, Sijie Huang, Xinheng He, Kai Wu, Xinyue Zhang, Dehua Yang, Xin Xie, H Eric Xu

引用次数: 0

Mechanistic insights into RNA cleavage by human Argonaute2–siRNA complex 人类Argonaute2-siRNA复合物裂解RNA的机制

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-16 DOI: 10.1038/s41422-025-01114-7

Zhenzhen Li, Qikui Xu, Yan Zhang, Jing Zhong, Tianxiang Zhang, Junchao Xue, Shuxian Liu, Haishan Gao, Z. Z. Zhao Zhang, Jianping Wu, En-Zhi Shen

{"title":"Mechanistic insights into RNA cleavage by human Argonaute2–siRNA complex","authors":"Zhenzhen Li, Qikui Xu, Yan Zhang, Jing Zhong, Tianxiang Zhang, Junchao Xue, Shuxian Liu, Haishan Gao, Z. Z. Zhao Zhang, Jianping Wu, En-Zhi Shen","doi":"10.1038/s41422-025-01114-7","DOIUrl":"https://doi.org/10.1038/s41422-025-01114-7","url":null,"abstract":"In animals, AGO-clade Argonaute proteins utilize small interfering RNAs (siRNAs) as guides to recognize target with complete complementarity, resulting in target RNA cleavage that is a critical step for target silencing. These proteins feature a constricted nucleic acid-binding channel that limits base pairing between the guide and target beyond the seed region. How the AGO–siRNA complexes overcome this structural limitation and achieve efficient target cleavage remains unclear. We performed cryo-electron microscopy of human AGO–siRNA complexes bound to target RNAs of increasing lengths to examine the conformational changes associated with target recognition and cleavage. Initially, conformational transition propagates from the opening of the PAZ domain and extends through a repositioning of the PIWI–L1–N domain toward the binding channel, facilitating the capture of siRNA–target duplex. Subsequent extension of base pairing drives the downward movement of the PIWI–L1–N domain to enable catalytic activation. Finally, further base pairing toward the 3′ end of siRNA destabilizes the PAZ–N domain, resulting in a “uni-lobed” architecture, which might facilitate the multi-turnover action of the AGO–siRNA enzyme complex. In contrast to PIWI-clade Argonautes, the “uni-lobed” structure of the AGO complex makes multiple contacts with the target in the central region of the siRNA–target duplex, positioning it within the catalytic site. Our findings shed light on the stepwise mechanisms by which the AGO–siRNA complex executes target RNA cleavage and offer insights into the distinct operational modalities of AGO and PIWI proteins in achieving such cleavage.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"16 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Why resident microglial-like cells were missed in the peripheral nervous system. 为什么周围神经系统中缺少常驻小胶质样细胞。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-04-15 DOI: 10.1038/s41422-025-01119-2

Michal Schwartz

引用次数: 0

Beyond peptide targeting sequences: machine learning of cellular condensate localization 超越肽靶向序列：细胞凝聚物定位的机器学习

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-14 DOI: 10.1038/s41422-025-01115-6

Jonathon A. Ditlev, Julie D. Forman-Kay

引用次数: 0