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231.
Protease-activated receptors (PARs) play a clear role in the burst of inflammatory reactions and immune responses. However,
for PAR-3, the most elusive member of the PAR family, the functional role is still largely unclear. It has been claimed that
PAR-3 does not signal autonomously, although the wide expression of human PAR-3 indicates its important physiological roles.
We demonstrate that in HEK-293 cells, stably transfected with human PAR-3, thrombin induced calcium signaling, IL-8 gene expression
and IL-8 release. We confirmed this finding using human lung epithelial and human astrocytoma cells that express endogenous
PAR-3. Moreover, thrombin exposure of HEK-293 cells resulted in ERK1/2 activation coinciding with IL-8 release. The effects
of thrombin were not dependent on PAR-1 activation, as confirmed by PAR-1 gene silencing. Thus, we propose that PAR-3 is able
to signal autonomously to induce IL-8 release mediated by ERK1/2 phosphorylation, which contributes actively to inflammatory
responses.
Received 9 December 2007; received after revision 16 January 2008; accepted 18 January 2008 相似文献
232.
Src-family kinases (SFKs) regulate different granulocyte and monocyte/macrophage responses. Accumulating evidence suggests that members of this family are implicated in signal transduction pathways regulating phagocytic cell migration and recruitment into inflammatory sites. Macrophages with a genetic deficiency of SFKs display marked alterations in cytoskeleton dynamics, polarization and migration. This same phenotype is found in cells with either a lack of SFK substrates and/or interacting proteins such as Pyk2/FAK, c-Cbl and p190RhoGAP. Notably, SFKs and their downstream targets also regulate monocyte recruitment into inflammatory sites. Depending on the type of assay used, neutrophil migration in vitro may be either dependent on or independent of SFKs. Also neutrophil recruitment in in vivo models of inflammation may be regulated differently by SFKs depending on the tissue involved. In this review we will discuss possible mechanisms by which SFKs may regulate phagocytic cell migratory abilities. 相似文献
233.
Molecular mechanisms of phagocytic uptake in mammalian cells 总被引:2,自引:1,他引:1
Groves E Dart AE Covarelli V Caron E 《Cellular and molecular life sciences : CMLS》2008,65(13):1957-1976
Phagocytosis is a highly conserved, complex process that has evolved to counter the constant threat posed by pathogens, effete cells and debris. Classically defined as a mechanism for internalising and destroying particles greater than 0.5 mum in size, it is a receptor-mediated, actin-driven process. The best-studied phagocytic receptors are the opsono-receptors, FcgammaR and CR3. Phagocytic uptake involves actin dynamics including polymerisation, bundling, contraction, severing and depolymerisation of actin filaments. Recent evidence points to the importance of membrane remodelling during phagocytosis, both in terms of changes in lipid composition and delivery of new membrane to the sites of particle binding. Here we review the molecular mechanisms of phagocytic uptake and some of the strategies developed by microbial pathogens to manipulate this process. 相似文献
234.
235.
Kao WH Klag MJ Meoni LA Reich D Berthier-Schaad Y Li M Coresh J Patterson N Tandon A Powe NR Fink NE Sadler JH Weir MR Abboud HE Adler SG Divers J Iyengar SK Freedman BI Kimmel PL Knowler WC Kohn OF Kramp K Leehey DJ Nicholas SB Pahl MV Schelling JR Sedor JR Thornley-Brown D Winkler CA Smith MW Parekh RS;Family Investigation of Nephropathy Diabetes Research Group 《Nature genetics》2008,40(10):1185-1192
As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans. 相似文献
236.
Two major functions of the Golgi apparatus (GA) are formation of complex glycans and sorting of proteins destined for various
subcellular compartments or secretion. To fulfill these tasks proper localization of the accessory proteins within the different
sub-compartments of the GA is crucial. Here we investigate structural determinants mediating transition of the two glycosyltransferases
β-1,4- galactosyltransferase 1 (gal-T1) and the α-1,3-fucosyltransferase 6 (fuc-T6) from the trans-Golgi cisterna to the trans-Golgi network (TGN). Upon treatment with the ionophore monensin both glycosyltransferases are found in TGN-derived swollen
vesicles, as determined by confocal fluorescence microscopy and density gradient fractionation. Both enzymes carry a signal
consisting of the amino acids E5P6 in gal-T1 and D2P3 in fuc-T6 necessary for the transition of these glycosyltransferases from the trans-Golgi cisterna to the TGN, but not for their steady state localization in the trans-Golgi cisterna.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 30 July 2008; received after revision 17 September 2008; accepted 29 September 2008 相似文献
237.
A. F. Vanin L. M. Bevers A. Slama-Schwok E. E. van Faassen 《Cellular and molecular life sciences : CMLS》2008,65(24):4066-4069
Announcement
Announcement 相似文献238.
It is generally thought that microtubule-associated motors insure long-range movements of the secretory vesicles from the center of the cell to its periphery, while myosins insure short-range movements at the cell periphery. However, several of the myosins that have been reported during the last decade to be involved in the exocytic pathway are not processive, meaning that they do not have the ability to move cargos along actin polymers. We will review here the possible mechanisms by which these myosins could contribute to the traffic of secretory proteins from the Golgi complex to the plasma membrane. 相似文献
239.
Papaconstantinou ME Gandhi PS Chen Z Bah A Di Cera E 《Cellular and molecular life sciences : CMLS》2008,65(22):3688-3697
Meizothrombin is the physiologically active intermediate generated by a single cleavage of prothrombin at R320 to separate the A and B chains. Recent evidence has suggested that meizothrombin, like thrombin, is a Na(+)-activated enzyme. In this study we present the first X-ray crystal structure of human meizothrombin desF1 solved in the presence of the active site inhibitor PPACK at 2.1 A resolution. The structure reveals a Na(+) binding site whose architecture is practically identical to that of human thrombin. Stopped-flow measurements of Na(+) binding to meizothrombin desF1 document a slow phase of fluorescence change with a k(obs) decreasing hyperbolically with increasing [Na(+)], consistent with the existence of three conformations in equilibrium, E*, E and E:Na(+), as for human thrombin. Evidence that meizothrombin exists in multiple conformations provides valuable new information for studies of the mechanism of prothrombin activation. 相似文献
240.
Uppal S Diggle CP Carr IM Fishwick CW Ahmed M Ibrahim GH Helliwell PS Latos-Bieleńska A Phillips SE Markham AF Bennett CP Bonthron DT 《Nature genetics》2008,40(6):789-793
Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary hypertrophic osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm. The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized. This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33-q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E(2) levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology. 相似文献