共查询到20条相似文献,搜索用时 9 毫秒
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Fine tuning of cell signals by glycosylation 总被引:1,自引:0,他引:1
Furukawa K Ohkawa Y Yamauchi Y Hamamura K Ohmi Y Furukawa K 《Journal of biochemistry》2012,151(6):573-578
Carbohydrates on the glycoproteins and glycosphingolipids expressed on the cell surface membrane play crucial roles in the determination of cell fates by being involved in the fine tuning of cell signalling as reaction molecules in the front line to various extrinsic stimulants. In glycoproteins, modification of proteins is performed by substitution of sugar chains to one or multiple sites of individual proteins, leading to quantitative and qualitative changes of receptor functions in the cell membrane. As for glycosphingolipids, majority of them consist of two moieties, i.e. carbohydrates and ceramides, and are localized in the microdomains such as lipid rafts or detergent-resistant microdomains. They generate and/or modulate cell signals to determine the cell fates by interacting with various carbohydrate-recognizing proteins. Modes of glycosylation and mechanisms by which glycosylation is involved in the regulation of cell signals are now hot subjects in glycobiology. 相似文献
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Azzam HS DeJarnette JB Huang K Emmons R Park CS Sommers CL El-Khoury D Shores EW Love PE 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(9):5464-5472
Current data indicate that CD5 functions as an inhibitor of TCR signal transduction. Consistent with this role, thymocyte selection in TCR transgenic/CD5(-/-) mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift from positive toward negative selection. An explanation for the variable effect of CD5 on selection is suggested by the observation that CD5 surface expression is regulated by TCR signal intensity during development and CD5 surface levels on mature thymocytes and T cells parallel the avidity of the positively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then examined the effect of CD5 overexpression or CD5 deletion (CD5(-/-)) on selection of thymocytes that express the same TCR transgenes. The results demonstrate that the effect on thymocyte selection of altering CD5 expression depends on the avidity of the selecting interaction and, consequently, the level of basal (endogenous) CD5 surface expression. Substitution of endogenous CD5 with a transgene encoding a truncated form of the protein failed to rescue the CD5(-/-) phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indicate that inducible regulation of CD5 surface expression during thymocyte selection functions to fine tune the TCR signaling response. 相似文献
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Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads 总被引:9,自引:0,他引:9 下载免费PDF全文
Murakami G Watabe T Takaoka K Miyazono K Imamura T 《Molecular biology of the cell》2003,14(7):2809-2817
Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads for bone morphogenetic proteins (BMPs) Smad1/5 and promotes their degradation. In addition, Smurf1 associates with transforming growth factor-beta type I receptor through the inhibitory Smad (I-Smad) Smad7 and induces their degradation. Herein, we examined whether Smurf1 negatively regulates BMP signaling together with the I-Smads Smad6/7. Smurf1 and Smad6 cooperatively induced secondary axes in Xenopus embryos. Using a BMP-responsive promoter-reporter construct in mammalian cells, we found that Smurf1 cooperated with I-Smad in inhibiting BMP signaling and that the inhibitory activity of Smurf1 was not necessarily correlated with its ability to bind to Smad1/5 directly. Smurf1 bound to BMP type I receptors via I-Smads and induced ubiquitination and degradation of these receptors. Moreover, Smurf1 associated with Smad1/5 indirectly through I-Smads and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms. 相似文献
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Muckenthaler MU 《Cell metabolism》2008,8(1):1-3
Hepcidin, the systemic regulator of iron homeostasis is activated by proteins responsible for hereditary hemochromatosis, bone morphogenetic proteins (BMPs), and inflammatory cytokines. Three recent publications now identify a novel hepcidin suppressor, the transmembrane serine protease TMPRSS6 (also known as matriptase-2), which is required to sense iron deficiency. 相似文献
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Based on our extensive studies of D-glucosidase inhibiting 2,5-dideoxy-2,5-imino-D-mannitol derivatives, we have been trying to create a series of fluorescent derivatives with a view to an 'inhibitory activity ruler' based on competitive displacement reactions of non-fluorescent inhibitors by fluorescent ones and vice versa, which can be performed and followed in microtiter plates or on-chips. Thus, a set of compounds was assembled with Ki values between 2 nM and 1 microM against Agrobacterium sp. beta-glucosidase. 相似文献
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Riojas RA Kikani CK Wang C Mao X Zhou L Langlais PR Hu D Roberts JL Dong LQ Liu F 《The Journal of biological chemistry》2006,281(31):21588-21593
3-Phosphoinositide-dependent protein kinase-1 (PDK1) mediates phosphorylation and activation of members of the AGC protein kinase family and plays an essential role in insulin signaling and action. However, whether and how PDK1 activity is regulated in cells remains largely uncharacterized. In the present study, we show that PDK1 undergoes insulin-stimulated and phosphatidylinositol 3-kinase-dependent phosphorylation at Ser244 in the activation loop and at a novel site: Ser163 in the hinge region between the two lobes of the kinase domain. Sequence alignment studies revealed that the residue corresponding to Ser163 of PDK1 in all other AGC kinases is glutamate, suggesting that a negative charge at this site may be important for PDK1 function. Replacing Ser163 with a negatively charged residue, glutamate, led to a 2-fold increase in PDK1 activity. Molecular modeling studies suggested that phosphorylated Ser163 may form additional hydrogen bonds with Tyr149 and Gln223. In support of this, mutation of Tyr149 to Ala is sufficient to reduce PDK1 activity. Taken together, our results suggest that PDK1 phosphorylation of Ser163 may provide a mechanism to fine-tune PDK1 activity and function in cells. 相似文献
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TGF-beta and the Smad signal transduction pathway. 总被引:31,自引:0,他引:31
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Liu C Gaça MD Swenson ES Vellucci VF Reiss M Wells RG 《The Journal of biological chemistry》2003,278(13):11721-11728
Hepatic stellate cells are the primary cell type responsible for matrix deposition in liver fibrosis, undergoing a process of transdifferentiation into fibrogenic myofibroblasts. These cells, which undergo a similar transdifferentiation process when cultured in vitro, are a major target of the profibrogenic agent transforming growth factor-beta (TGF-beta). We have studied activation of the TGF-beta downstream signaling molecules Smads 2, 3, and 4 in hepatic stellate cells (HSC) cultured in vitro for 1, 4, and 7 days, with quiescent, intermediate, and fully transdifferentiated phenotypes, respectively. Total levels of Smad4, common to multiple TGF-beta superfamily signaling pathways, do not change as HSC transdifferentiate, and the protein is found in both nucleus and cytoplasm, independent of treatment with TGF-beta or the nuclear export inhibitor leptomycin B. TGF-beta mediates activation of Smad2 primarily in early cultured cells and that of Smad3 primarily in transdifferentiated cells. The linker protein SARA, which is required for Smad2 signaling, disappears with transdifferentiation. Additionally, day 7 cells demonstrate constitutive phosphorylation and nuclear localization of Smad 2, which is not affected by pretreatment with TGF-beta-neutralizing antibodies, a type I TGF-beta receptor kinase inhibitor, or activin-neutralizing antibodies. These results demonstrate essential differences between TGF-beta-mediated signaling pathways in quiescent and in vitro transdifferentiated hepatic stellate cells. 相似文献
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Fine tuning of cell functions through remodeling of glycosphingolipids by plasma membrane-associated glycohydrolases 总被引:1,自引:0,他引:1
Sandro Sonnino Massimo Aureli Nicoletta Loberto Vanna Chigorno Alessandro Prinetti 《FEBS letters》2010,584(9):1914-1922
The plasma membrane (PM) sphingolipid composition is the result of a series of well-known metabolic pathways comprising neobiosynthesis in the endoplasmic reticulum and in the Golgi apparatus followed by vesicular delivery to the plasma membrane, membrane turnover with final catabolism in lysosomes, and shedding of membrane components. In addition to this, the head group of PM sphingolipids can be opportunely modified by the action of PM associated hydrolases and transferases. The number of enzymes for glycosphingolipid metabolism that have been shown to be associated with the plasma membrane and the information on their properties are growing very rapidly. In this review, we will focus on the possible role and on the involvement of the plasma membrane-associated glycohydrolases in modulating cell functions. 相似文献
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Roy E Togbe D Holdorf A Trubetskoy D Nabti S Küblbeck G Schmitt S Kopp-Schneider A Leithäuser F Möller P Bladt F Hämmerling GJ Arnold B Pawson T Tafuri A 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(12):7518-7526
Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire. 相似文献