近几年来,关于哺乳动物雷帕霉素靶(mammalian target of rapamycin,mTOR)在各种哺乳动物细胞中调节肌动蛋白微丝极化及肌球蛋白微丝网形成的研究一直在不断地取得新的进展。尽管到目前为止,包括mTORC2上游和下游在内的相关的调控路径还...近几年来,关于哺乳动物雷帕霉素靶(mammalian target of rapamycin,mTOR)在各种哺乳动物细胞中调节肌动蛋白微丝极化及肌球蛋白微丝网形成的研究一直在不断地取得新的进展。尽管到目前为止,包括mTORC2上游和下游在内的相关的调控路径还未明确,但是因为mTORC的生物学多样性,使其成为了当今生物学研究的焦点之一。基于长久以来特别是近五年对mTORC2的研究,在涉及细胞运动迁移、增殖分化、蛋白质合成、凋亡及自噬等生物学功能的研究中,一些重要的下游相关调控分子和蛋白相继被发现,比如P-Rex1/2、Rho家族GTPases、PKC、cAMP、p27Kip1等。该综述着重总结了mTORC2实现这些生物学功能所可能通过的四条路径。当然,仍然需要大量的实验数据和研究证据进一步地证实和完善这些已经发现的可能存在的路径。展开更多
The Rictor/mTOR complex plays a pivotal role in a variety of cellular functions including cellular metabolism,cell proliferation and survival by phosphorylating Akt at Ser473 to fully activate the Akt kinase.However,i...The Rictor/mTOR complex plays a pivotal role in a variety of cellular functions including cellular metabolism,cell proliferation and survival by phosphorylating Akt at Ser473 to fully activate the Akt kinase.However,its upstream regulatory pathways as well as whether it has additional function(s)remain largely unknown.We recently reported that Rictor contains a novel ubiquitin E3 ligase activity by forming a novel complex with Cullin-1,but not with other Cullin family members.Furthermore,we identified SGK1 as its downstream target.Interestingly,Rictor,but not Raptor or mTOR,promotes SGK1 ubiquitination.As a result,SGK1 expression is elevated in Rictor^(–/–)MEFs.We further defined that as a feedback mechanism,Rictor can be phosphorylated by multiple AGC family kinases including Akt,S6K and SGK1.Phosphorylation of Rictor at the Thr1135 site did not affect its kinase activity towards phosphorylating its conventional substrates including Akt and SGK1.On the other hand,it disrupted the interaction between Rictor and Cullin-1.Consequently,T1135E Rictor was defective in promoting SGK1 ubiquitination and destruction.This finding further expands our knowledge of Rictor’s function.Furthermore,our work also illustrates that Rictor E3 ligase activity could be governed by specific signaling kinase cascades,and that misregulation of this process might contribute to SGK overexpression which is frequently observed in various types of cancers.展开更多
Spinal cord injury(SCI)causes neuroinflammation,neuronal death,and severe axonal connections.Alleviating neuroinflammation,protecting residual cells and promoting neuronal regeneration via endogenous neural stem cells...Spinal cord injury(SCI)causes neuroinflammation,neuronal death,and severe axonal connections.Alleviating neuroinflammation,protecting residual cells and promoting neuronal regeneration via endogenous neural stem cells(eNSCs)represent potential strategies for SCI treatment.Extracellular vesicles(EVs)released by mesenchymal stem cells have emerged as pathological mediators and alternatives to cell-based therapies following SCI.In the present study,EVs isolated from untreated(control,C-EVs)and TGF-β1-treated(T-EVs)mesenchymal stem cells were injected into SCI mice to compare the therapeutic effects and explore the underlying mechanisms.Our study demonstrated for the first time that the application of T-EVs markedly enhanced the proliferation and antiapoptotic ability of NSCs in vitro.The infusion of T-EVs into SCI mice increased the shift from the M1 to M2 polarization of reactive microglia,alleviated neuroinflammation,and enhanced the neuroprotection of residual cells during the acute phase.Moreover,T-EVs increased the number of eNSCs around the epicenter.Consequently,T-EVs further promoted neurite outgrowth,increased axonal regrowth and remyelination,and facilitated locomotor recovery in the chronic stage.Furthermore,the use of T-EVs in Rictor/SCI mice(conditional knockout of Rictor in NSCs)showed that T-EVs failed to increase the activation of eNSCs and improve neurogenesis sufficiently,which suggested that T-EVs might induce the activation of eNSCs by targeting the mTORC2/Rictor pathway.Taken together,our findings indicate the prominent role of T-EVs in the treatment of SCI,and the therapeutic efficacy of T-EVs for SCI treatment might be optimized by enhancing the activation of eNSCs via the mTORC2/Rictor signaling pathway.展开更多
文摘近几年来,关于哺乳动物雷帕霉素靶(mammalian target of rapamycin,mTOR)在各种哺乳动物细胞中调节肌动蛋白微丝极化及肌球蛋白微丝网形成的研究一直在不断地取得新的进展。尽管到目前为止,包括mTORC2上游和下游在内的相关的调控路径还未明确,但是因为mTORC的生物学多样性,使其成为了当今生物学研究的焦点之一。基于长久以来特别是近五年对mTORC2的研究,在涉及细胞运动迁移、增殖分化、蛋白质合成、凋亡及自噬等生物学功能的研究中,一些重要的下游相关调控分子和蛋白相继被发现,比如P-Rex1/2、Rho家族GTPases、PKC、cAMP、p27Kip1等。该综述着重总结了mTORC2实现这些生物学功能所可能通过的四条路径。当然,仍然需要大量的实验数据和研究证据进一步地证实和完善这些已经发现的可能存在的路径。
基金supported in part by the DOD Prostate New Investigator award to W.W.NIH grant GM089763 to W.W.
文摘The Rictor/mTOR complex plays a pivotal role in a variety of cellular functions including cellular metabolism,cell proliferation and survival by phosphorylating Akt at Ser473 to fully activate the Akt kinase.However,its upstream regulatory pathways as well as whether it has additional function(s)remain largely unknown.We recently reported that Rictor contains a novel ubiquitin E3 ligase activity by forming a novel complex with Cullin-1,but not with other Cullin family members.Furthermore,we identified SGK1 as its downstream target.Interestingly,Rictor,but not Raptor or mTOR,promotes SGK1 ubiquitination.As a result,SGK1 expression is elevated in Rictor^(–/–)MEFs.We further defined that as a feedback mechanism,Rictor can be phosphorylated by multiple AGC family kinases including Akt,S6K and SGK1.Phosphorylation of Rictor at the Thr1135 site did not affect its kinase activity towards phosphorylating its conventional substrates including Akt and SGK1.On the other hand,it disrupted the interaction between Rictor and Cullin-1.Consequently,T1135E Rictor was defective in promoting SGK1 ubiquitination and destruction.This finding further expands our knowledge of Rictor’s function.Furthermore,our work also illustrates that Rictor E3 ligase activity could be governed by specific signaling kinase cascades,and that misregulation of this process might contribute to SGK overexpression which is frequently observed in various types of cancers.
基金supported by the Fundamental Research Funds for the Central Universities(No.21623310)the Dongguan Science and Technology of Social Development Program(No.20231800939902)+3 种基金the National Natural Science Foundation of China(No.81801907)the Guangdong Basic and Applied Basic Research Foundation(No.2022A1515140171)the Medical Joint Fund of Jinan University(No.YXJC2022011)Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research(No.ZDSYS20230626091402006).
文摘Spinal cord injury(SCI)causes neuroinflammation,neuronal death,and severe axonal connections.Alleviating neuroinflammation,protecting residual cells and promoting neuronal regeneration via endogenous neural stem cells(eNSCs)represent potential strategies for SCI treatment.Extracellular vesicles(EVs)released by mesenchymal stem cells have emerged as pathological mediators and alternatives to cell-based therapies following SCI.In the present study,EVs isolated from untreated(control,C-EVs)and TGF-β1-treated(T-EVs)mesenchymal stem cells were injected into SCI mice to compare the therapeutic effects and explore the underlying mechanisms.Our study demonstrated for the first time that the application of T-EVs markedly enhanced the proliferation and antiapoptotic ability of NSCs in vitro.The infusion of T-EVs into SCI mice increased the shift from the M1 to M2 polarization of reactive microglia,alleviated neuroinflammation,and enhanced the neuroprotection of residual cells during the acute phase.Moreover,T-EVs increased the number of eNSCs around the epicenter.Consequently,T-EVs further promoted neurite outgrowth,increased axonal regrowth and remyelination,and facilitated locomotor recovery in the chronic stage.Furthermore,the use of T-EVs in Rictor/SCI mice(conditional knockout of Rictor in NSCs)showed that T-EVs failed to increase the activation of eNSCs and improve neurogenesis sufficiently,which suggested that T-EVs might induce the activation of eNSCs by targeting the mTORC2/Rictor pathway.Taken together,our findings indicate the prominent role of T-EVs in the treatment of SCI,and the therapeutic efficacy of T-EVs for SCI treatment might be optimized by enhancing the activation of eNSCs via the mTORC2/Rictor signaling pathway.
