共查询到20条相似文献，搜索用时 31 毫秒
1.
Bohn LM Lefkowitz RJ Gainetdinov RR Peppel K Caron MG Lin FT 《Science (New York, N.Y.)》1999,286(5449):2495-2498
The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the mu opioid receptor (muOR). The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with beta-arrestin 1 and beta-arrestin 2. Functional deletion of the beta-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that muOR desensitization was impaired. These results provide evidence in vivo for the physiological importance of beta-arrestin 2 in regulating the function of a specific GPCR, the muOR. Moreover, they suggest that inhibition of beta-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence. 相似文献
2.
Hobson JP Rosenfeldt HM Barak LS Olivera A Poulton S Caron MG Milstien S Spiegel S 《Science (New York, N.Y.)》2001,291(5509):1800-1803
EDG-1 is a heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) for sphingosine-1-phosphate (SPP). Cell migration toward platelet-derived growth factor (PDGF), which stimulates sphingosine kinase and increases intracellular SPP, was dependent on expression of EDG-1. Deletion of edg-1 or inhibition of sphingosine kinase suppressed chemotaxis toward PDGF and also activation of the small guanosine triphosphatase Rac, which is essential for protrusion of lamellipodia and forward movement. Moreover, PDGF activated EDG-1, as measured by translocation of beta-arrestin and phosphorylation of EDG-1. Our results reveal a role for receptor cross-communication in which activation of a GPCR by a receptor tyrosine kinase is critical for cell motility. 相似文献
3.
Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, there has been little evidence connecting ubiquitination with regulation of mammalian G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) function. Agonist stimulation of endogenous or transfected beta2-adrenergic receptors (beta2ARs) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta-arrestin. Moreover, proteasome inhibitors reduced receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta2AR. Receptor ubiquitination required beta-arrestin, which bound to the E3 ubiquitin ligase Mdm2. Abrogation of beta-arrestin ubiquitination, either by expression in Mdm2-null cells or by dominant-negative forms of Mdm2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, a beta2AR mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. These findings delineate an adapter role of beta-arrestin in mediating the ubiquitination of the beta2AR and indicate that ubiquitination of the receptor and of beta-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic GPCR. 相似文献
4.
Wang Q Zhao J Brady AE Feng J Allen PB Lefkowitz RJ Greengard P Limbird LE 《Science (New York, N.Y.)》2004,304(5679):1940-1944
Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with receptor-Gbetagamma complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of alpha2 adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses. 相似文献
5.
Matsuzawa A Tseng PH Vallabhapurapu S Luo JL Zhang W Wang H Vignali DA Gallagher E Karin M 《Science (New York, N.Y.)》2008,321(5889):663-668
Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Indeed, CD40, a tumor necrosis factor receptor (TNFR) family member, forms a complex containing adaptor molecules TRAF2 and TRAF3, ubiquitin-conjugating enzyme Ubc13, cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2), IkappaB kinase regulatory subunit IKKgamma (also called NEMO), and mitogen-activated protein kinase (MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKKgamma were required for complex assembly and activation of MEKK1 and MAPK cascades. However, these kinases were not activated unless the multicomponent signaling complex translocated from CD40 to the cytosol upon c-IAP1/2-induced degradation of TRAF3. This two-stage signaling mechanism may apply to other innate immune receptors, accounting for spatial and temporal separation of MAPK and IKK signaling. 相似文献
6.
Chen W Ren XR Nelson CD Barak LS Chen JK Beachy PA de Sauvage F Lefkowitz RJ 《Science (New York, N.Y.)》2004,306(5705):2257-2260
Binding of Sonic Hedgehog (Shh) to Patched (Ptc) relieves the latter's tonic inhibition of Smoothened (Smo), a receptor that spans the cell membrane seven times. This initiates signaling which, by unknown mechanisms, regulates vertebrate developmental processes. We find that two molecules interact with mammalian Smo in an activation-dependent manner: G protein-coupled receptor kinase 2 (GRK2) leads to phosphorylation of Smo, and beta-arrestin 2 fused to green fluorescent protein interacts with Smo. These two processes promote endocytosis of Smo in clathrin-coated pits. Ptc inhibits association of beta-arrestin 2 with Smo, and this inhibition is relieved in cells treated with Shh. A Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by GRK2 and interaction of beta-arrestin 2 with Smo. beta-Arrestin 2 and GRK2 are thus potential mediators of signaling by activated Smo. 相似文献
7.
Sasaki T Irie-Sasaki J Jones RG Oliveira-dos-Santos AJ Stanford WL Bolon B Wakeham A Itie A Bouchard D Kozieradzki I Joza N Mak TW Ohashi PS Suzuki A Penninger JM 《Science (New York, N.Y.)》2000,287(5455):1040-1046
Phosphoinositide 3-kinases (PI3Ks) regulate fundamental cellular responses such as proliferation, apoptosis, cell motility, and adhesion. Viable gene-targeted mice lacking the p110 catalytic subunit of PI3Kgamma were generated. We show that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells. PI3Kgamma-deficient neutrophils exhibited severe defects in migration and respiratory burst in response to heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) agonists and chemotactic agents. PI3Kgamma links GPCR stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase, and extracellular signal-regulated kinases 1 and 2. Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst. 相似文献
8.
M J Lohse J L Benovic J Codina M G Caron R J Lefkowitz 《Science (New York, N.Y.)》1990,248(4962):1547-1550
Homologous or agonist-specific desensitization of beta-adrenergic receptors is thought to be mediated by a specific kinase, the beta-adrenergic receptor kinase (beta ARK). However, recent data suggest that a cofactor is required for this kinase to inhibit receptor function. The complementary DNA for such a cofactor was cloned and found to encode a 418-amino acid protein homologous to the retinal protein arrestin. The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors. 相似文献
9.
Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4 总被引：1，自引：0，他引：1
Chen W ten Berge D Brown J Ahn S Hu LA Miller WE Caron MG Barak LS Nusse R Lefkowitz RJ 《Science (New York, N.Y.)》2003,301(5638):1391-1394
Wnt proteins, regulators of development in many organisms, bind to seven transmembrane-spanning (7TMS) receptors called frizzleds, thereby recruiting the cytoplasmic molecule dishevelled (Dvl) to the plasma membrane.Frizzled-mediated endocytosis of Wg (a Drosophila Wnt protein) and lysosomal degradation may regulate the formation of morphogen gradients. Endocytosis of Frizzled 4 (Fz4) in human embryonic kidney 293 cells was dependent on added Wnt5A protein and was accomplished by the multifunctional adaptor protein beta-arrestin 2 (betaarr2), which was recruited to Fz4 by binding to phosphorylated Dvl2. These findings provide a previously unrecognized mechanism for receptor recruitment of beta-arrestin and demonstrate that Dvl plays an important role in the endocytosis of frizzled, as well as in promoting signaling. 相似文献
10.
Rakhilin SV Olson PA Nishi A Starkova NN Fienberg AA Nairn AC Surmeier DJ Greengard P 《Science (New York, N.Y.)》2004,306(5696):698-701
Calmodulin (CaM) is a major effector for the intracellular actions of Ca2+ in nearly all cell types. We identified a CaM-binding protein, designated regulator of calmodulin signaling (RCS). G protein-coupled receptor (GPCR)-dependent activation of protein kinase A (PKA) led to phosphorylation of RCS at Ser55 and increased its binding to CaM. Phospho-RCS acted as a competitive inhibitor of CaM-dependent enzymes, including protein phosphatase 2B (PP2B, also called calcineurin). Increasing RCS phosphorylation blocked GPCR- and PP2B-mediated suppression of L-type Ca2+ currents in striatal neurons. Conversely, genetic deletion of RCS significantly increased this modulation. Through a molecular mechanism that amplifies GPCR- and PKA-mediated signaling and attenuates GPCR- and PP2B-mediated signaling, RCS synergistically increases the phosphorylation of key proteins whose phosphorylation is regulated by PKA and PP2B. 相似文献
11.
Pouysségur J 《Science (New York, N.Y.)》2000,290(5496):1515-1518
12.
半番鸭与番鸭精巢组织差异表达转录组测序分析 总被引：2，自引：2，他引：0
【目的】研究半番鸭与番鸭精巢组织转录组差异表达基因,为进一步阐明半番鸭不育的遗传机制奠定理论基础。【方法】利用转录组测序方法对半番鸭和番鸭的精巢组织进行研究,筛选其差异表达基因,并对其功能进行注释和荧光定量PCR(quantitative real-time PCR,QRT-PCR)验证。【结果】测序共获得43.84Gb Clean Data,组装后共获得193 535条Unigene。DESeq分析发现3 597个基因在两个鸭品种间差异表达,其中上调基因1 194个和下调基因2 403个,包括与生殖功能相关的基因,如成纤维细胞生长因子(fibroblast growth factor,FGF)、蛋白激酶A(protein kinase A,PKA)、丝裂原活化蛋白激酶7(mitogen-activated protein kinase 7-like,partial,BMK)、生长因子受体结合蛋白2(growth factor receptor-bound protein 2,GRB2)、c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)和肿瘤坏死因子受体超家族成员6(tumor necrosis factor receptor superfamily member 6,FAS)等。GO(gene Ontology)分析发现382个差异基因获得功能注释,其中97个基因涉及发育繁殖生物学过程。KEGG(kyoto Encyclopedia of Genes and Genomes)通路分析表明差异表达基因共富集到50条信号通路中,其中17个通路显著富集,包括丝裂原活化蛋白激酶信号转导通路(mitogen-activated protein kinase signaling pathway,MAPK)、甘油酯代谢(glycerolipid metabolism)以及钙信号途径(calcium signaling pathway)信号通路等,与生殖功能密切相关的有促性腺激素释放激素信号通路(gonadotropin releasing hormone(Gn RH)signaling pathway)和MAPK信号转导通路。经QRT-PCR验证,差异基因表达变化模式与转录组测序结果一致,测序结果可靠。【结论】在转录组水平上筛选出半番鸭和番鸭精巢组织差异表达基因,揭示了Gn RH和MAPK信号通路在鸭的生殖活动中发挥了重要作用,为进一步探索半番鸭生殖系统的分化机理提供可靠的参考依据。 相似文献
13.
Chen W Kirkbride KC How T Nelson CD Mo J Frederick JP Wang XF Lefkowitz RJ Blobe GC 《Science (New York, N.Y.)》2003,301(5638):1394-1397
beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well. 相似文献
14.
Intracellular signaling networks receive and process information to control cellular machines. The mitogen-activated protein kinase (MAPK) 1,2/protein kinase C (PKC) system is one such network that regulates many cellular machines, including the cell cycle machinery and autocrine/paracrine factor synthesizing machinery. We used a combination of computational analysis and experiments in mouse NIH-3T3 fibroblasts to understand the design principles of this controller network. We find that the growth factor-stimulated signaling network containing MAPK 1, 2/PKC can operate with one (monostable) or two (bistable) stable states. At low concentrations of MAPK phosphatase, the system exhibits bistable behavior, such that brief stimulus results in sustained MAPK activation. The MAPK-induced increase in the amounts of MAPK phosphatase eliminates the prolonged response capability and moves the network to a monostable state, in which it behaves as a proportional response system responding acutely to stimulus. Thus, the MAPK 1, 2/PKC controller network is flexibly designed, and MAPK phosphatase may be critical for this flexible response. 相似文献
15.
Regulation of bone phosphorus retention and bone development possibly by BMP and MAPK signaling pathways in broilers 
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下载免费PDF全文 LIAO Xiu-dong CAO Su-mei LI Ting-ting SHAO Yu-xin ZHANG Li-yang LU Lin ZHANG Ri-jun HOU Shui-sheng LUO Xu-gang 《农业科学学报》2022,21(10):3017-3025
The bone morphogenetic protein (BMP) and mitogen-activated protein kinase (MAPK) signaling pathways play an important role in regulation of bone formation and development, however, it remains unclear that the effect of dietary different levels of non-phytate phosphorus (NPP) on these signaling pathways and their correlations with bone phosphorus (P) retention and bone development in broilers. Therefore, this experiment was conducted to investigate the effect of dietary P supplementation on BMP and MAPK signaling pathways and their correlations with bone P retention and bone development in broilers. A total of 800 one-day-old Arbor Acres male broilers were randomly allotted to 1 of 5 treatments with 8 replicates in a completely randomized design. The 5 treatments of dietary NPP levels were 0.15, 0.25, 0.35, 0.45 and 0.55% or 0.15, 0.22, 0.29, 0.36 and 0.43% for broilers from 1 to 21 days of age or 22 to 42 days of age, respectively. The results showed that extracellular signal-regulated kinase 1 (ERK1) mRNA expression in the tibia of broilers on days 14 and 28, phosphorylated-ERK1 (p-ERK1) on day 14, and BMP2 protein expression on days 28 and 42 decreased linearly (P<0.04), while c-Jun N-terminal kinase 1 (JNK1) mRNA expression on day 42 increased linearly (P<0.02) with the increase of dietary NPP level. At 14 days of age, total P accumulation in tibia ash (TPTA), bone mineral concentration (BMC), bone mineral density (BMD), bone breaking strength (BBS) and tibia ash were negatively correlated (r=–0.726 to –0.359, P<0.05) with ERK1 and JNK1 mRNA as well as p-ERK1; tibia alkaline phosphatase (ALP) and bone gal protein (BGP) were positively correlated (r=0.405 to 0.665, P<0.01) with ERK1 mRNA and p-ERK1. At 28 days of age, TPTA, BMC, BMD, BBS and tibia ash were negatively correlated (r=–0.518 to –0.370, P<0.05) with ERK1 mRNA and BMP2 protein, while tibia ALP was positively correlated (r=0.382 to 0.648, P<0.05) with them. The results indicated that TPTA, BMC, BMD, BBS or tibia ash had negative correlations, while tibia ALP and BGP had positive correlations with ERK1 and JNK1 mRNAs, BMP2 protein and p-ERK1, suggesting that bone P retention and bone development might be regulated by BMP and MAPK signaling pathways in broiler chickens. 相似文献
16.
肉仔鸡卫星细胞氧化应激时MAPK信号通路 总被引：1，自引：0，他引：1
【目的】在地塞米松(DEX)诱导骨骼肌卫星细胞氧化应激的体外条件下,筛选丝裂原活化蛋白激酶(MAPKs)信号系统中起关键作用的信号通路。【方法】 将体外培养的肉仔鸡胸肌骨骼肌卫星细胞(SCs)分别进行处理：Ⅰ、对照组;Ⅱ、DEX;Ⅲ、p38 MAPK抑制剂;Ⅳ、DEX+p38 MAPK抑制剂;Ⅴ、JNK抑制剂;Ⅵ、DEX+JNK抑制剂;Ⅶ、ERK5抑制剂;Ⅷ、DEX+ERK5抑制剂;Ⅸ、ERK1/2抑制剂;Ⅹ、DEX+ERK 1/2抑制剂。除处理Ⅰ和处理Ⅱ外,其它处理首先用抑制剂预处理30 min,弃去培养基后,再按处理设置分别加入含DEX的培养基或者正常培养基继续处理24 h。处理结束后,分别测定细胞培养液中丙二醛(MDA)、活性氧自由基(ROS)、超氧化物歧化酶(SOD)和谷胱甘肽硫转酶(GST)含量或活性;同时采用RT-PCR方法检测通路蛋白及SOD与GST基因表达量。【结果】 抑制剂单独处理组MDA和ROS的产生量显著低于DEX处理(P＜0.05);DEX+ERK5抑制剂处理与DEX+ERK 1/2抑制剂处理的MDA和ROS产生量显著高于ERK 5抑制剂处理和ERK1/2抑制剂处理(P＜0.05); DEX+p38 MAPK抑制剂处理与 DEX+JNK抑制剂处理组的MDA和ROS产生量与p38 MAPK处理和JNK处理的差异不显著(P＞0.05)。抑制剂单独处理组的SOD和GST活性比DEX处理高(P＜0.01);DEX+ERK5抑制剂处理与 DEX+ERK 1/2抑制剂处理的SOD和GST活性极显著低于ERK5抑制剂处理组和ERK1/2抑制剂处理组(P＜0.01),DEX+p38 MAPK抑制剂处理与DEX+JNK抑制剂处理的SOD和GST活性与p38 MAPK抑制剂处理和 JNK抑制剂处理的差异不显著(P＞0.05)。基因表达结果表明,DEX能够抑制GST和SOD基因的表达,抑制率达37%以上。与抑制ERK5和ERK1/2通路不同,抑制p38 MAPK和JNK通路后,DEX对GST和SOD基因的表达无明显抑制作用。【结论】 在DEX诱导的肉仔鸡胸肌骨骼肌SCs产生的氧化应激过程中,p38 MAPK和JNK通路起着关键作用。 相似文献
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18.
拟南芥COI 1互作基因的分离 总被引：1，自引：1，他引：1
为进一步阐明茉莉素调控植物生长发育的分子机理，为作物抗性和雄性不育基因工程提供新思路，以COI1为诱饵，利用酵母双杂交分析体系筛选拟南芥cDNA文库，得到300多个阳性克隆，经PCR，RsaⅠ酶切PCR产物以后归为12群，从代表菌落提取pB42AD cDNA重组质粒进行了测序，完成了序列分析，得到ASK1，COAP2，COAP3，COAP4等12个基因，其中ASK1，COAP2，COAP3等基因与Skp1等重要基因有较高的同源性。 相似文献
19.
Pagès G Guérin S Grall D Bonino F Smith A Anjuere F Auberger P Pouysségur J 《Science (New York, N.Y.)》1999,286(5443):1374-1377
The p42 and p44 mitogen-activated protein kinases (MAPKs), also called Erk2 and Erk1, respectively, have been implicated in proliferation as well as in differentiation programs. The specific role of the p44 MAPK isoform in the whole animal was evaluated by generation of p44 MAPK-deficient mice by homologous recombination in embryonic stem cells. The p44 MAPK-/- mice were viable, fertile, and of normal size. Thus, p44 MAPK is apparently dispensable and p42 MAPK (Erk2) may compensate for its loss. However, in p44 MAPK-/- mice, thymocyte maturation beyond the CD4+CD8+ stage was reduced by half, with a similar diminution in the thymocyte subpopulation expressing high levels of T cell receptor (CD3high). In p44 MAPK-/- thymocytes, proliferation in response to activation with a monoclonal antibody to the T cell receptor in the presence of phorbol myristate acetate was severely reduced even though activation of p42 MAPK was more sustained in these cells. The p44 MAPK apparently has a specific role in thymocyte development. 相似文献
20.
Cells reuse signaling proteins in multiple pathways, raising the potential for improper cross talk. Scaffold proteins are thought to insulate against such miscommunication by sequestering proteins into distinct physical complexes. We show that the scaffold protein Ste5, which organizes the yeast mating mitogen-activated protein kinase (MAPK) pathway, does not use sequestration to prevent misactivation of the mating response. Instead, Ste5 appears to use a conformation mechanism: Under basal conditions, an intramolecular interaction of the pleckstrin homology (PH) domain with the von Willebrand type A (VWA) domain blocks the ability to coactivate the mating-specific MAPK Fus3. Pheromone-induced membrane binding of Ste5 triggers release of this autoinhibition. Thus, in addition to serving as a conduit guiding kinase communication, Ste5 directly receives input information to decide if and when signal can be transmitted to mating output. 相似文献