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The PI3K/Akt pathway, one of the most frequently dysregulated signaling pathways in various cancers, plays a key role in tumorigenesis and resistance to chemotherapy. Recent discovery highlights an important regulatory step where Smurf1-mediated PDK1 neddylation through poly-Nedd8 chains is an early event for oncogenic Akt activation in KRAS-mutant colorectal cancer.The phosphoinositide 3-kinase (PI3K)/Akt axis regulates diverse biological processes including cell proliferation, survival, apoptosis, and metabolism critical for tumorigenesis.1 The activation of Akt, a critical downstream effector of PI3K, is central for cancer development.

PI3K/Akt通路是各种癌症中最常失调的信号通路之一，在肿瘤发生和化疗耐药中起着关键作用。最近的发现突出了一个重要的调控步骤，其中Smurf1通过poly-Nedd8链介导的PDK1 neddylation是KRAS突变型结直肠癌中致癌Akt激活的早期事件。磷酸肌醇3-激酶（PI3K）/Akt轴调节多种生物学过程，包括对肿瘤发生至关重要的细胞增殖，存活，凋亡和代谢。Akt是PI3K的关键下游效应子，其激活是癌症发展的核心。

While the mechanisms underlying Akt activation have been extensively characterized in literature,2 intensive ongoing research continues to advance our understanding of Akt activation. In a recent paper published in Nature Chemical Biology, Peng et al.3 identified SMAD ubiquitylation regulatory factor 1 (Smurf1)-mediated PDK1 neddylation as an early event for Akt activation upon growth factor treatment and subsequent downstream oncogenic signaling in KRAS-mutated colorectal cancer (CRC).It is well established that PI3K activated by growth factors catalyzes the production of PIP3 at the plasma membrane (PM), which recruits cytosolic inactive PDK1 and Akt to the PM through its binding to the pleckstrin homology (PH) domain of these proteins.

虽然Akt激活的潜在机制已在文献中得到广泛表征，但2正在进行的深入研究继续推进我们对Akt激活的理解。在最近发表在《自然化学生物学》上的一篇论文中，Peng等[3]将SMAD泛素化调节因子1（Smurf1）介导的PDK1 neddylation鉴定为生长因子治疗后Akt活化的早期事件，以及随后在KRAS突变的结直肠癌（CRC）中的下游致癌信号传导。众所周知，由生长因子激活的PI3K催化质膜（PM）上PIP3的产生，质膜（PM）通过与这些蛋白质的pleckstrin同源性（PH）结构域结合，将胞质无活性PDK1和Akt募集到PM。

Subsequently, PDK1 phosphorylates Akt at Thr308 and mTORC2 at Ser473 for full activation of Akt.4 Apart from PI3K, post-translational modifications (PTMs) including methylation and ubiquitination of Akt are also critical early events for PM translocation and activation of Akt.5,6,7 Upon growth factor stimulation, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) interacts with and meth.

随后，PDK1在Thr308磷酸化Akt，在Ser473磷酸化mTORC2以完全激活Akt。除PI3K外，包括Akt甲基化和泛素化在内的翻译后修饰（PTM）也是PM易位和Akt活化的关键早期事件。生长因子刺激后，SET结构域分叉的组蛋白赖氨酸甲基转移酶1（SETDB1）与meth相互作用。

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Download referencesAuthor informationAuthor notesThese authors contributed equally: Rajesh kumar Manne, Rajni Kant.Authors and AffiliationsDepartment of Pathology, School of Medicine, Duke University, Durham, NC, USARajesh Kumar Manne, Rajni Kant & Hui-Kuan LinAuthorsRajesh Kumar ManneView author publicationsYou can also search for this author in.

下载参考文献作者信息作者注释这些作者做出了同样的贡献：Rajesh kumar Manne，Rajni Kant。作者和附属机构杜克大学医学院病理学系，北卡罗来纳州达勒姆，USARajesh Kumar Manne，Rajni Kant＆Hui Kuan Linauthors Rajesh Kumar ManneView作者出版物您也可以在中搜索该作者。

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Hui-Kuan Lin.Rights and permissionsReprints and permissionsAbout this articleCite this articleManne, R.K., Kant, R. & Lin, HK. PDK1 neddylation by Smurf1 drives Akt activation.

林惠宽。权利和许可打印和许可本文引用本文Manne，R.K.，Kant，R。＆Lin，HK。Smurf1的PDK1 neddylation驱动Akt激活。

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