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941.
Gutiérrez-López MD Gilsanz A Yáñez-Mó M Ovalle S Lafuente EM Domínguez C Monk PN González-Alvaro I Sánchez-Madrid F Cabañas C 《Cellular and molecular life sciences : CMLS》2011,68(19):3275-3292
ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell
surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important
biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report
here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ
proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association
between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert
negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against
its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction,
negatively regulates the sheddase activity of ADAM17. 相似文献
942.
Pan Q Qiao F Gao C Norman B Optican L Zelenka PS 《Cellular and molecular life sciences : CMLS》2011,68(20):3425-3436
The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In
normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent
ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work
has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75).
Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability
of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation,
is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75
or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent
cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life
is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src
and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75)
is a physiologically significant mechanism of regulating intracellular Src activity. 相似文献
943.
Rodríguez-Muñoz M Sánchez-Blázquez P Vicente-Sánchez A Bailón C Martín-Aznar B Garzón J 《Cellular and molecular life sciences : CMLS》2011,68(17):2933-2949
A series of pharmacological and physiological studies have demonstrated the functional cross-regulation between MOR and NMDAR.
These receptors coexist at postsynaptic sites in midbrain periaqueductal grey (PAG) neurons, an area implicated in the analgesic
effects of opioids like morphine. In this study, we found that the MOR-associated histidine triad nucleotide-binding protein
1 (HINT1) is essential for maintaining the connection between the NMDAR and MOR. Morphine-induced analgesic tolerance is prevented
and even rescued by inhibiting PKC or by antagonizing NMDAR. However, in the absence of HINT1, the MOR becomes supersensitive
to morphine before suffering a profound and lasting desensitization that is refractory to PKC inhibition or NMDAR antagonism.
Thus, HINT1 emerges as a key protein that is critical for sustaining NMDAR-mediated regulation of MOR signaling strength.
Thus, HINT1 deficiency may contribute to opioid-intractable pain syndromes by causing long-term MOR desensitization via mechanisms
independent of NMDAR. 相似文献
944.
Important to the function of calpains is temporal and spatial regulation of their proteolytic activity. Here, we demonstrate
that cytoplasm-resident calpain 2 cleaves human nuclear topoisomerase I (hTOP1) via Ca2+-activated proteolysis and nucleoplasmic shuttling of proteases. This proteolysis of hTOP1 was induced by either ionomycin-caused
Ca2+ influx or addition of Ca2+ in cellular extracts. Ca2+ failed to induce hTOP1 proteolysis in calpain 2-knockdown cells. Moreover, calpain 2 cleaved hTOP1 in vitro. Furthermore,
calpain 2 entered the nucleus upon Ca2+ influx, and calpastatin interfered with this process. Calpain 2 cleavage sites were mapped at K158 and K183 of hTOP1. Calpain 2-truncated hTOP1 exhibited greater relaxation activity but remained able to interact with nucleolin and
to form cleavable complexes. Interestingly, calpain 2 appears to be involved in ionomycin-induced protection from camptothecin-induced
cytotoxicity. Thus, our data suggest that nucleocytoplasmic shuttling may serve as a novel type of regulation for calpain
2-mediated nuclear proteolysis. 相似文献
945.
946.
叶片式混输泵气液两相流及性能的数值分析 总被引:1,自引:0,他引:1
利用Fluent计算软件在多重参考坐标系下采用欧拉方法的双流体湍流模型计算螺旋轴流式叶片泵内高含气状态下的三维气液两相流场.通过对泵内绝对流速、叶轮相对流速、静态压力、气液两相分布及其相间滑移速度矢量的分析,探讨了气液两相介质在泵内的流动规律.结果显示离心力的作用使叶轮内液相主要在轮缘附近流动,而气相则聚集在轮毂附近;泵导叶内气液两相分离状况有较明显改善.通过与泵性能实验结果对比,验证了文中方法对气液两相叶片式混输泵计算分析的有效性. 相似文献
947.
黄骏 《华南理工大学学报(自然科学版)》2007,35(11):32-35
广州地铁的网络化发展正在逐步走向成熟,城市公共空间在"以公交为导向"的城市规划理念(TOD)下,依托地铁发展,有效地整合功能和建立有地域性特征的发展模式是其中的关键环节.文中通过对现状和问题的分析、比较研究,用系统科学的方法,提出以地铁车站为核心、步行系统为联系纽带,形成网络化的站域公共空间体系. 相似文献
948.
对温度场中碳纤维薄板(CFL)增强钢筋混凝土(RC)梁在不同破坏模式下的承载能力进行理论分析.研究结果表明,环境温度的变化对CFL增强RC梁的承载能力有一定程度的影响:(1)当环境温度升高30K时,CFL厚度分别为0.1、0.2、0.3和0.4mm的增强RC梁的开裂载荷分别提高了5.37%、10.46%、15.9%和20.94%;(2)CFL厚度为0.1mm和0.2mm的增强RC梁的破坏模式为CFL拉断,其极限承载力随环境温度的升高呈下降趋势,但降低幅度小于3.5%;(3)CFL厚度为0.3mm和0.4mm的增强RC梁的破坏模式为混凝土压碎,其极限承载力随环境温度的升高呈上升趋势,但升高幅度小于3.5%. 相似文献
949.
为研究软弱夹层对边坡失稳的影响,对含软弱夹层的岩体强度及破坏模式进行了理论和试验研究.采用某边坡钻孔芯样分别制备强风化泥岩、泥化夹层、含软弱夹层泥岩3种三轴试样,并进行三轴固结不排水剪试验.结合理论分析,对强风化泥岩、泥化夹层、含软弱夹层泥岩的强度和破坏模式进行了研究,揭示软弱夹层倾角、围压对试样强度和破坏模式的影响规... 相似文献
950.