CD40诱导Ras亚型到亚细胞区室的选择性通路

IF 3.6 3区 生物学 Q3 CELL BIOLOGY
Arathi Nair, Sushmita Chakraborty, Bhaskar Saha
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引用次数: 0

摘要

Ras gtpase是细胞信号传导和肿瘤发生的核心。Ras基因的三个位点编码四种蛋白质亚型,即Harvey-Ras (H-Ras)、Kirsten-Ras (K-Ras 4A和4B)和Neuroblastoma-Ras (N-Ras),它们具有80%的序列相似性,过去被认为是功能冗余的。Ras的小分子抑制剂缺乏对同种异构体的特异性,导致Ras靶向治疗中广泛的毒性。Ras亚型的组织特异性表达和与癌变、胚胎发育和感染的选择性关联表明它们的非冗余性。我们发现,抗原提呈细胞(APC)表达的免疫受体CD40可诱导H-Ras、K-Ras和N-Ras选择性地迁移到质膜(PM)脂筏、线粒体、内质网(ER),但不会迁移到高尔基复合体(GC)。与具有聚赖氨酸残基的非棕榈酰化K-Ras (4B)相比,两种棕榈酰化Ras亚型- h -Ras和n- Ras -在早期时间点具有相似的共定位模式,进入PM的富脂筏微域。cd40诱导的H-Ras和K-Ras向线粒体和内质网的转运与N-Ras相似但不同。所有Ras亚型向GC的运输不依赖于CD40刺激。受体驱动的转运和H-Ras、K-Ras和N-Ras的空间分离暗示了Ras亚型的功能非冗余的亚型特异性亚细胞信号传导平台。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

CD40 induces selective routing of Ras isoforms to subcellular compartments

CD40 induces selective routing of Ras isoforms to subcellular compartments

Ras GTPases are central to cellular signaling and oncogenesis. The three loci of the Ras gene encode for four protein isoforms namely Harvey-Ras (H-Ras), Kirsten-Ras (K-Ras 4A and 4B), and Neuroblastoma-Ras (N-Ras) which share ~ 80% sequence similarity and used to be considered functionally redundant. The small molecule inhibitors of Ras lack specificity for the isoforms leading to widespread toxicity in Ras-targeted therapeutics. Ras isoforms’ tissue-specific expression and selective association with carcinogenesis, embryonic development, and infection suggested their non-redundancy. We show that CD40, an antigen-presenting cell (APC)-expressed immune receptor, induces selective relocation of H-Ras, K-Ras, and N-Ras to the Plasma membrane (PM) lipid rafts, mitochondria, endoplasmic reticulum (ER), but not to the Golgi complex (GC). The two palmitoylated Ras isoforms—H-Ras and N-Ras—have a similar pattern of colocalization into the lipid-rich raft microdomain of the PM at early time points when compared to non-palmitoylated K-Ras (4B) with polylysine residues. CD40-induced trafficking of H-Ras and K-Ras to mitochondria and ER was found to be similar but different from that of N-Ras. Trafficking of all the Ras isoforms to the GC was independent of CD40 stimulation. The receptor-driven trafficking and spatial segregation of H-Ras, K-Ras, and N-Ras imply isoform-specific subcellular signaling platforms for the functional non-redundancy of Ras isoforms.

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来源期刊
CiteScore
6.40
自引率
4.90%
发文量
40
期刊介绍: The Journal of Cell Communication and Signaling provides a forum for fundamental and translational research. In particular, it publishes papers discussing intercellular and intracellular signaling pathways that are particularly important to understand how cells interact with each other and with the surrounding environment, and how cellular behavior contributes to pathological states. JCCS encourages the submission of research manuscripts, timely reviews and short commentaries discussing recent publications, key developments and controversies. Research manuscripts can be published under two different sections : In the Pathology and Translational Research Section (Section Editor Andrew Leask) , manuscripts report original research dealing with celllular aspects of normal and pathological signaling and communication, with a particular interest in translational research. In the Molecular Signaling Section (Section Editor Satoshi Kubota) manuscripts report original signaling research performed at molecular levels with a particular interest in the functions of intracellular and membrane components involved in cell signaling.
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