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排序方式: 共有735条查询结果,搜索用时 156 毫秒
81.
SN Shehata RW Hunter E Ohta MW Peggie HJ Lou F Sicheri E Zeqiraj BE Turk K Sakamoto 《Cellular signalling》2012,24(11):2085-2094
PCTAIRE-1 (cyclin-dependent kinase [CDK] 16) is a highly conserved serine/threonine kinase that belongs to the CDK family of protein kinases. Little is known regarding PCTAIRE-1 regulation and function and no robust assay exists to assess PCTAIRE-1 activity mainly due to a lack of information regarding its preferred consensus motif and the lack of bona fide substrates. We used positional scanning peptide library technology and identified the substrate-specificity requirements of PCTAIRE-1 and subsequently elaborated a peptide substrate termed PCTAIRE-tide. Recombinant PCTAIRE-1 displayed vastly improved enzyme kinetics on PCTAIRE-tide compared to a widely used generic CDK substrate peptide. PCTAIRE-tide also greatly improved detection of endogenous PCTAIRE-1 activity. Similar to other CDKs, PCTAIRE-1 requires a proline residue immediately C-terminal to the phosphoacceptor site (+1) for optimal activity. PCTAIRE-1 has a unique preference for a basic residue at +4, but not at +3 position (a key characteristic for CDKs). We also demonstrate that PCTAIRE-1 binds to a novel cyclin family member, cyclin Y, which increased PCTAIRE-1 activity towards PCTAIRE-tide >100-fold. We hypothesised that cyclin Y binds and activates PCTAIRE-1 in a way similar to which cyclin A2 binds and activates CDK2. Point mutants of cyclin Y predicted to disrupt PCTAIRE-1-cyclin Y binding severely prevented complex formation and activation of PCTAIRE-1. We have identified PCTAIRE-tide as a powerful tool to study the regulation of PCTAIRE-1. Our understanding of the molecular interaction between PCTAIRE-1 and cyclin Y further facilitates future investigation of the functions of PCTAIRE-1 kinase. 相似文献
82.
Liu S Xie Z Zhao Q Pang H Turk J Calderon L Su W Zhao G Xu H Gong MC Guo Z 《The Journal of biological chemistry》2012,287(29):24739-24753
Whether group VIA phospholipase A(2) (iPLA(2)β) is involved in vascular inflammation and neointima formation is largely unknown. Here, we report that iPLA(2)β expression increases in the vascular tunica media upon carotid artery ligation and that neointima formation is suppressed by genetic deletion of iPLA(2)β or by inhibiting its activity or expression via perivascular delivery of bromoenol lactone or of antisense oligonucleotides, respectively. To investigate whether smooth muscle-specific iPLA(2)β is involved in neointima formation, we generated transgenic mice in which iPLA(2)β is expressed specifically in smooth muscle cells and demonstrate that smooth muscle-specific expression of iPLA(2)β exacerbates ligation-induced neointima formation and enhanced both production of proinflammatory cytokines and vascular infiltration by macrophages. With cultured vascular smooth muscle cell, angiotensin II, arachidonic acid, and TNF-α markedly induce increased expression of IL-6 and TNF-α mRNAs, all of which were suppressed by inhibiting iPLA(2)β activity or expression with bromoenol lactone, antisense oligonucleotides, and genetic deletion, respectively. Similar suppression also results from genetic deletion of 12/15-lipoxygenase or inhibiting its activity with nordihydroguaiaretic acid or luteolin. Expression of iPLA(2)β protein in cultured vascular smooth muscle cells was found to depend on the phenotypic state and to rise upon incubation with TNF-α. Our studies thus illustrate that smooth muscle cell-specific iPLA(2)β participates in the initiation and early progression of vascular inflammation and neointima formation and suggest that iPLA(2)β may represent a novel therapeutic target for preventing cardiovascular diseases. 相似文献
83.
Albert Wong Yuan-Wei Zhang Grace R. Jeschke Benjamin E. Turk Gary Rudnick 《The Journal of biological chemistry》2012,287(43):36051-36058
The serotonin transporter (SERT) is responsible for reuptake of serotonin (5-hydroxytryptamine) after its exocytotic release from neurons. It is the primary target for antidepressants and stimulants, including “ecstasy” (3,4-methylenedioxymethamphetamine). SERT is regulated by several processes, including a cyclic GMP signaling pathway involving nitric oxide synthase, guanylyl cyclase, and cGMP-dependent protein kinase (PKG). Here, we show that SERT was phosphorylated in a PKG Iα-dependent manner in vitro, but that SERT was not a direct substrate of PKG. We generated an analog-sensitive gatekeeper residue mutant of PKG Iα (M438G) that efficiently used the ATP analog N6-benzyl-ATP. This mutant, but not the wild type (WT) kinase, used the ATP analog to phosphorylate both a model peptide substrate as well as an established protein substrate of PKG (vasodilator-stimulated phosphoprotein). PKG Iα M438G effectively substituted for the WT kinase in stimulating SERT-mediated 5-hydroxytryptamine transport in cultured cells. Addition of either WT or mutant PKG Iα M438G to membranes containing SERT in vitro led to radiolabel incorporation from [γ-33P]ATP but not from similarly labeled N6-benzyl-ATP, indicating that SERT was phosphorylated by another kinase that could not utilize the ATP analog. These results are consistent with the proposed SERT phosphorylation site, Thr-276, being highly divergent from the consensus PKG phosphorylation site sequence, which we verified through peptide library screening. Another proposed SERT kinase, the p38 mitogen-activated protein kinase, could not substitute for PKG in this assay, and p38 inhibitors did not block PKG-dependent phosphorylation of SERT. The results suggest that PKG initiates a kinase cascade that leads to phosphorylation of SERT by an as yet unidentified protein kinase. 相似文献
84.
Rojnik M Jevnikar ZR Doljak B Turk S Zidar N Kos J 《European journal of cell biology》2012,91(10):757-764
Cathepsin H is a unique member of the cysteine cathepsins that acts primarily as an aminopeptidase. Like other cysteine cathepsins, it is synthesized as an inactive precursor and activated by proteolytic removal of its propeptide. Here we demonstrate that, in human cells, the processing of the propeptide is an autocatalytic, multistep process proceeding from an inactive 41kDa pro-form, through a 30kDa intermediate form, to the 28kDa mature form. Tyr87P and Gly90P were identified as the two major endopeptidase cleavage sites, converting the 30kDa form into the mature 28kDa form. The level of processing differs significantly in different human cell lines. In monocyte-derived macrophages U937 and prostate cancer cells PC-3, the 28kDa form is predominant, whereas in osteoblasts HOS the processing from the 30kDa form to the 28kDa form is significantly lower. The aminopeptidase activity of the enzyme and its subcellular localization are independent of the product, however the 30kDa form was not secreted in HOS cells. The activity of the resulting cathepsin H in U937 cells was significantly lower than that in HOS cells, presumably due to the high levels of endogenous cysteine protease inhibitor cystatin F present specifically in this cell line. These results provide an insight into the dependence of human cathepsin H processing and regulation on cell type. 相似文献
85.
Protease signalling: the cutting edge 总被引:1,自引:0,他引:1
Protease research has undergone a major expansion in the last decade, largely due to the extremely rapid development of new technologies, such as quantitative proteomics and in-vivo imaging, as well as an extensive use of in-vivo models. These have led to identification of physiological substrates and resulted in a paradigm shift from the concept of proteases as protein-degrading enzymes to proteases as key signalling molecules. However, we are still at the beginning of an understanding of protease signalling pathways. We have only identified a minor subset of true physiological substrates for a limited number of proteases, and their physiological regulation is still not well understood. Similarly, links with other signalling systems are not well established. Herein, we will highlight current challenges in protease research. 相似文献
86.
The aim of this study was to investigate (i) the cholecystokinin, somatostatin and apelin mRNA levels, (ii) the changes in levels and localization of these peptides, (iii) relation between these peptides, (iv) antiapoptotic effects and (v) antioxidant effects of ghrelin. The rats were divided into four groups second day after birth. These groups were respectively treated with physiological saline, ghrelin (100μg/kg/day), streptozotocin (100mg/kg), ghrelin and streptozotocin. After four weeks, small intestine and blood samples were taken from rats. Cholecystokinin mRNA and peptide, somatostatin mRNA, release to duodenal lumen of apelin peptide and apelin mRNA signals decreased in ghrelin-treated diabetic rats compared to the diabetic group. There was no statistically significant difference among the four groups for somatostatin and apelin peptides. Caspase-3 signals were not observed only in diabetic group treated with ghrelin. Caspase-8 signals were increased while PCNA signals were decreased in diabetic group given ghrelin compared to diabetic group. Small intestine CAT, SOD, GP(x) and GST activities and GSH levels were decreased and LPO, PC levels were increased in diabetic rats. Administration of ghrelin to diabetic rats caused an increase in intestinal CAT, SOD, GP(x) and GST activities and GSH levels, while PC levels decreased. As a result, we observed positive changes in diabetic rats treated with ghrelin in both microscopic and biochemical studies. We can suggest that ghrelin may be an important hormone for the treatment of diabetes. 相似文献
87.
M Sinreih I Sosič N Beranič S Turk AO Adeniji TM Penning TL Rižner S Gobec 《Bioorganic & medicinal chemistry letters》2012,22(18):5948-5951
Human aldo-keto reductases AKR1C1-AKR1C3 are involved in the biosynthesis and inactivation of steroid hormones and prostaglandins and thus represent attractive targets for the development of new drugs. We synthesized a series of N-benzoyl anthranilic acid derivatives and tested their inhibitory activity on AKR1C enzymes. Our data show that these derivatives inhibit AKR1C1-AKR1C3 isoforms with low micromolar potency. In addition, five selective inhibitors of AKR1C3 were identified. The most promising inhibitors were compounds 10 and 13, with IC(50) values of 0.31μM and 0.35μM for AKR1C3, respectively. 相似文献
88.
Milk is one of the most important nutrients for humans during lifetime. Farm animal milk in all its products like cheese and other fermentation and transformation products is a widespread nutrient for the entire life of humans. Proteins are key molecules of the milk functional component repertoire and their investigation represents a major challenge. Proteins in milk, such as caseins, contribute to the formation of micelles that are different from species to species in dimension and casein-type composition; they are an integral part of the MFGM (Milk Fat Globule Membrane) that has being exhaustively studied in recent years. Milk proteins can act as enzymes or have an antimicrobial activity; they could act as hormones and, last but not least, they have a latent physiological activity encoded in their primary structure that turns active when the protein is cleaved by fermentation or digestion processes. In this review we report the last progress in proteomics, peptidomics and bioinformatics. These new approaches allow us to better characterize the milk proteome of farm animal species, to highlight specific PTMs, the peptidomic profile and even to predict the potential nutraceutical properties of the analyzed proteins. 相似文献
89.
90.