Phosphorylation of Acinus Regulates its Biological Functions

腺泡磷酸化调节其生物学功能

• 批准号: 8403526
• 负责人: KEQIANG YE
• 金额: $ 32.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403526
• 关键词: Acinus organ component; Affect; Alternative Splicing; Apoptosis; Apoptotic; Arginine; Back; Binding; Biological; Biological Process; C-terminal; Caspase; Cell Nucleus; Cell Survival; Cell physiology; Chromatin; Cleaved cell; DNA Fragmentation; Drug Targeting; Enzymes; Feeds; Goals; Histones; Knowledge; Mediating; Molecular; Neurodegenerative Disorders; Neurons; Nuclear; Patients; Phosphorylation; Phosphotransferases; Physical condensation; Physiological; Play; Process; Protein Kinase; Proteins; RNA Processing; RNA Recognition Motif; Rattus; Regulation; Research; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Stimulus; Testing; Two-Hybrid System Techniques; Yeasts; abstracting; caspase-3; excitotoxicity; feeding; hippocampal pyramidal neuron; insight; neuronal survival; novel; prevent; protein kinase C-delta; research study; upstream kinase

Phosphorylation of Acinus Regulates its Biological Functions Abstract Acinus (apoptotic chromatin condensation inducer in the nucleus) is cleaved during apoptosis by caspases to produce a 17-kDa fragment (p17), triggering apoptotic chromatin condensation prior to DNA fragmentation. AMPA-induced excitotoxicity increases nuclear levels of caspase-activated acinus and incurs chromatin condensation in rat hippocampal pyramidal neurons. Acinus localizes in the nuclear speckle and contains an RNA-recognition motif (RRM), followed by a C-terminal serine and arginine rich (SR) domain. The highly conserved SR proteins are key players in the control of alternative splicing. Recently, we showed that Akt phosphorylates acinus and enhances its resistance to caspase cleavage and inhibits acinus-dependent chromatin condensation. Moreover, the p17 fragment initiates H2B phosphorylation and chromatin condensation through activating PKC-¿. Our preliminary studies reveal that acinus binds SRPK2, an SR protein specific kinase, which phosphorylates acinus. Interestingly, Akt also phosphorylates SRPK2. However, whether this phosphorylation by SRPK2 regulates acinus proteolytic degradation in neurons remains unknown. Further, we found that PKC-¿ feeds back and phosphorylates acinus, stimulating its apoptotic degradation, but the physiological significance of this phosphorylation is unclear. The significance and physiological consequence of these interactions in neuronal survival remains elusive. We hypothesize that acinus is a physiological substrate of PKC-¿ and SRPK2, and the coordinate phosphorylation by these kinases will delicately define the physiological roles of acinus in neurons. Identification of signaling pathways mediating acinus phosphorylation, proteolytic degradation and apoptotic activity is essential for understanding not only the physiological functions of acinus, but also the upstream crosstalk dictating the nuclear apoptotic machinery in neurons.

腺泡的磷酸化调节其生物学功能 抽象的 在胱天蛋白酶凋亡过程中，刺激性（细胞核中的凋亡染色质凝结诱导剂）被切割至 产生17 kDa片段（P17），在DNA片段化之前触发凋亡染色质凝结。 AMPA诱导的兴奋性毒性增加了caspase激活的核水平，并导致染色质 大鼠海马锥体神经元的缩合。 acinus位于核斑点中，并包含一个 RNA识别基序（RRM），然后是C末端丝氨酸和精氨酸（SR）结构域。高度 保守的SR蛋白是控制替代剪接的关键参与者。最近，我们证明了Akt 磷酸化并增强其对胱天蛋白酶裂解的抵抗力，并抑制腺苷依赖性染色质 缩合。此外，p17片段启动了H2B的磷酸化和染色质缩合 激活PKC-。我们的初步研究表明，Acinus结合SRPK2，SRPK2，一种SR蛋白特异性激酶，该激酶是该蛋白质的。 磷酸化刺激。有趣的是，AKT还磷酸化SRPK2。但是，这种磷酸化是否 通过SRPK2调节神经元中蛋白水解降解仍然未知。此外，我们发现PKC-- 反馈并磷酸化刺激，刺激其凋亡降解，但物理意义 这种磷酸化尚不清楚。这些相互作用的意义和身体后果 神经元生存仍然难以捉摸。我们假设acinus是PKC-¿的物理底物，并且 SRPK2和这些激酶的坐标磷酸化将清楚地定义 神经元中的刺激。鉴定介导促磷酸化，蛋白水解的信号通路 降解和凋亡活性不仅可以理解acinus的物理功能，还至关重要 而且还决定神经元中的核凋亡机制。

项目成果

Multiple functions of phosphoinositide-3 kinase enhancer (PIKE).

• DOI: 10.1100/tsw.2010.64
• 发表时间: 2010-04-13
• 期刊: TheScientificWorldJournal
• 作者: Chan CB;Ye K
• 通讯作者: Ye K

Serine-arginine protein kinases: new players in neurodegenerative diseases?

• DOI: 10.1515/revneuro-2013-0014
• 发表时间: 2013-08-01
• 期刊: REVIEWS IN THE NEUROSCIENCES
• 影响因子: 4.1
• 作者: Chan, Chi Bun;Ye, Keqiang
• 通讯作者: Ye, Keqiang

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.

抑制 δ 分泌酶可改善阿尔茨海默病小鼠模型的认知功能

• DOI: 10.1038/ncomms14740
• 发表时间: 2017-03-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Zhang Z;Obianyo O;Dall E;Du Y;Fu H;Liu X;Kang SS;Song M;Yu SP;Cabrele C;Schubert M;Li X;Wang JZ;Brandstetter H;Ye K
• 通讯作者: Ye K

NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association.

• DOI: 10.1038/onc.2009.236
• 发表时间: 2009-10-29
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Chan, C. B.;Liu, X.;Jang, S-W;Hsu, S. I-H;Williams, I.;Kang, S.;Chen, J.;Ye, K.
• 通讯作者: Ye, K.