共查询到20条相似文献，搜索用时 46 毫秒
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He L Lu XY Jolly AF Eldridge AG Watson SJ Jackson PK Barsh GS Gunn TM 《Science (New York, N.Y.)》2003,299(5607):710-712
mahoganoid is a mouse coat-color mutation whose pigmentary phenotype and genetic interactions resemble those of Attractin (Atrn). Atrn mutations also cause spongiform neurodegeneration. Here, we show that a null mutation for mahoganoid causes a similar age-dependent neuropathology that includes many features of prion diseases but without accumulation of protease-resistant prion protein. The gene mutated in mahoganoid encodes a RING-containing protein with E3 ubiquitin ligase activity in vitro. Similarities in phenotype, expression, and genetic interactions suggest that mahoganoid and Atrn genes are part of a conserved pathway for regulated protein turnover whose function is essential for neuronal viability. 相似文献
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Huang YH Grasis JA Miller AT Xu R Soonthornvacharin S Andreotti AH Tsoukas CD Cooke MP Sauer K 《Science (New York, N.Y.)》2007,316(5826):886-889
Pleckstrin homology (PH) domain-mediated protein recruitment to cellular membranes is of paramount importance for signal transduction. The recruitment of many PH domains is controlled through production and turnover of their membrane ligand, phosphatidylinositol 3,4,5-trisphosphate (PIP3). We show that phosphorylation of the second messenger inositol 1,4,5-trisphosphate (IP3) into inositol 1,3,4,5-tetrakisphosphate (IP4) establishes another mode of PH domain regulation through a soluble ligand. At physiological concentrations, IP4 promoted PH domain binding to PIP3. In primary mouse CD4+CD8+ thymocytes, this was required for full activation of the protein tyrosine kinase Itk after T cell receptor engagement. Our data suggest that IP4 establishes a feedback loop of phospholipase C-gamma1 activation through Itk that is essential for T cell development. 相似文献
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An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control 总被引：67，自引：0，他引：67
T G Boulton G D Yancopoulos J S Gregory C Slaughter C Moomaw J Hsu M H Cobb 《Science (New York, N.Y.)》1990,249(4964):64-67
A protein kinase characterized by its ability to phosphorylate microtubule-associated protein-2 (MAP2), is thought to be an early intermediate in an insulin-stimulated phosphorylation cascade and in a variety of other mammalian cell responses to extracellular signals. A complementary DNA that encodes this protein serine-threonine kinase has been cloned, and the protein designated extracellular signal-regulated kinase 1 (ERK1). ERK1 has striking similarity to two protein kinases, KSS1 and FUS3, from yeast. The yeast kinases function in an antagonistic manner to regulate the cell cycle in response to mating factors. Thus, ERK1 and the two yeast kinases constitute a family of evolutionarily conserved enzymes involved in regulating the response of eukaryotic cells to extracellular signals. 相似文献
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Fos-associated protein p39 is the product of the jun proto-oncogene 总被引：109，自引：0，他引：109
F J Rauscher D R Cohen T Curran T J Bos P K Vogt D Bohmann R Tjian B R Franza 《Science (New York, N.Y.)》1988,240(4855):1010-1016
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Plant development: regulation by protein degradation 总被引：2，自引：0，他引：2
Many aspects of eukaryotic development depend on regulated protein degradation by the ubiquitin-proteasome pathway. This highly conserved pathway promotes covalent attachment of ubiquitin to protein substrates through the sequential action of three enzymes called a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3). Most ubiquitinated proteins are then targeted for degradation by the 26S proteasome. Recent studies have also shown that the ubiquitin-related protein RUB/Nedd8 and the proteasome-related COP9 signalosome complex cooperate with the ubiquitin-proteasome pathway to promote protein degradation. Most of these components are conserved in all three eukaryotic kingdoms. However, the known targets of the pathway in plants, and the developmental processes they regulate, are specific to the plant kingdom. 相似文献
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Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling 总被引：1，自引：0，他引：1
Yu Y Yoon SO Poulogiannis G Yang Q Ma XM Villén J Kubica N Hoffman GR Cantley LC Gygi SP Blenis J 《Science (New York, N.Y.)》2011,332(6035):1322-1326
The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1. 相似文献
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Kolas NK Chapman JR Nakada S Ylanko J Chahwan R Sweeney FD Panier S Mendez M Wildenhain J Thomson TM Pelletier L Jackson SP Durocher D 《Science (New York, N.Y.)》2007,318(5856):1637-1640
Cells respond to DNA double-strand breaks by recruiting factors such as the DNA-damage mediator protein MDC1, the p53-binding protein 1 (53BP1), and the breast cancer susceptibility protein BRCA1 to sites of damaged DNA. Here, we reveal that the ubiquitin ligase RNF8 mediates ubiquitin conjugation and 53BP1 and BRCA1 focal accumulation at sites of DNA lesions. Moreover, we establish that MDC1 recruits RNF8 through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM). We also show that depletion of the E2 enzyme UBC13 impairs 53BP1 recruitment to sites of damage, which suggests that it cooperates with RNF8. Finally, we reveal that RNF8 promotes the G2/M DNA damage checkpoint and resistance to ionizing radiation. These results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination. 相似文献
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Wang HR Zhang Y Ozdamar B Ogunjimi AA Alexandrova E Thomsen GH Wrana JL 《Science (New York, N.Y.)》2003,302(5651):1775-1779
The Rho family of small guanosine triphosphatases regulates actin cytoskeleton dynamics that underlie cellular functions such as cell shape changes, migration, and polarity. We found that Smurf1, a HECT domain E3 ubiquitin ligase, regulated cell polarity and protrusive activity and was required to maintain the transformed morphology and motility of a tumor cell. Atypical protein kinase C zeta (PKCzeta), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. Smurf1 thus links the polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signaling during dynamic membrane movements. 相似文献
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Gruber T Freeley M Thuille N Heit I Shaw S Long A Baier G 《Science (New York, N.Y.)》2006,312(5770):55; author reply 55
We observe that protein kinase C (PKC) is phosphorylated on the activation loop at threonine 538 (Thr-538) before T cell activation. Our results are inconsistent with the conclusions of Lee et al. (Reports, 1 April 2005, p. 114) that the Thr-538 phosphorylation of PKC is regulated by T cell receptor activation. Other mechanisms, such as autophosphorylation of Thr-219, might orchestrate the cellular function of PKC in T cells. 相似文献
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Dornan D Shimizu H Mah A Dudhela T Eby M O'rourke K Seshagiri S Dixit VM 《Science (New York, N.Y.)》2006,313(5790):1122-1126
The ataxia telangiectasia mutated (ATM) protein kinase is a critical component of a DNA-damage response network configured to maintain genomic integrity. The abundance of an essential downstream effecter of this pathway, the tumor suppressor protein p53, is tightly regulated by controlled degradation through COP1 and other E3 ubiquitin ligases, such as MDM2 and Pirh2; however, the signal transduction pathway that regulates the COP1-p53 axis following DNA damage remains enigmatic. We observed that in response to DNA damage, ATM phosphorylated COP1 on Ser(387) and stimulated a rapid autodegradation mechanism. Ionizing radiation triggered an ATM-dependent movement of COP1 from the nucleus to the cytoplasm, and ATM-dependent phosphorylation of COP1 on Ser(387) was both necessary and sufficient to disrupt the COP1-p53 complex and subsequently to abrogate the ubiquitination and degradation of p53. Furthermore, phosphorylation of COP1 on Ser(387) was required to permit p53 to become stabilized and to exert its tumor suppressor properties in response to DNA damage. 相似文献
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Thornton TM Pedraza-Alva G Deng B Wood CD Aronshtam A Clements JL Sabio G Davis RJ Matthews DE Doble B Rincon M 《Science (New York, N.Y.)》2008,320(5876):667-670
Glycogen synthase kinase 3beta (GSK3beta) is involved in metabolism, neurodegeneration, and cancer. Inhibition of GSK3beta activity is the primary mechanism that regulates this widely expressed active kinase. Although the protein kinase Akt inhibits GSK3beta by phosphorylation at the N terminus, preventing Akt-mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3beta substrate beta-catenin. Here, we show that p38 mitogen-activated protein kinase (MAPK) also inactivates GSK3beta by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of beta-catenin. p38 MAPK-mediated phosphorylation of GSK3beta occurs primarily in the brain and thymocytes. Activation of beta-catenin-mediated signaling through GSK3beta inhibition provides a potential mechanism for p38 MAPK-mediated survival in specific tissues. 相似文献
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Koepp DM Schaefer LK Ye X Keyomarsi K Chu C Harper JW Elledge SJ 《Science (New York, N.Y.)》2001,294(5540):173-177
Cyclin E binds and activates the cyclin-dependent kinase Cdk2 and catalyzes the transition from the G1 phase to the S phase of the cell cycle. The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro. Depletion of Fbw7 leads to accumulation and stabilization of cyclin E in vivo in human and Drosophila melanogaster cells. Multiple F-box proteins contribute to cyclin E stability in yeast, suggesting an overlap in SCF E3 ligase specificity that allows combinatorial control of cyclin E degradation. 相似文献
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高脂日粮对初情期小鼠乳腺发育的影响及分子机制 总被引：1，自引：1，他引：0
【目的】研究高脂日粮对初情期小鼠乳腺发育的影响及可能机制。【方法】选用20只4周龄昆明雌性小鼠,设对照组和高脂日粮组,试验期4周,每周称体质量并统计采食量。试验结束后采集小鼠乳腺并称质量,采用wholemount及HE染色观察小鼠乳腺组织形态结构及导管数量。利用Western blot检测初情期小鼠乳腺组织胰岛素样生长因子1(Insulin-like growth factor1,IGF-1)、增殖相关信号通路关键蛋白蛋白激酶B(Protein kinase B,Akt)、胞外调控的蛋白激酶(Extracellular regulated protein kinase,Er K)以及炎症信号通路关键蛋白Toll样受体4(Toll-like receptor 4,TLR4)、c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)和核因子κB激酶抑制剂(Inhibitor of nuclear factor kappa-B kinase,IKK)的表达。【结果】高脂日粮组小鼠采食量极显著低于对照组(P0.01),但在能量摄入方面与对照组无显著差异。高脂日粮组小鼠的体质量增加显著高于对照组(P0.05)。高脂日粮组小鼠在乳腺质量、乳腺质量与体质量的比值上均极显著高于对照组(P0.01)。乳腺组织的whole-mount及HE染色结果表明,高脂日粮组小鼠乳腺导管发育明显被抑制,其乳腺组织的导管数和密度明显降低,乳腺组织的终末乳芽数量也极显著低于对照组(P0.01)。高脂日粮能够显著抑制小鼠乳腺组织IGF-I的蛋白表达以及Akt、Erk和IKK的磷酸化水平(P0.01或0.05),极显著促进小鼠乳腺组织TLR4的蛋白表达(P0.01)和显著促进JNK的磷酸化水平(P0.05)。【结论】高脂日粮能够抑制初情期小鼠乳腺发育,这可能是通过抑制乳腺增殖的相关信号和促进乳腺组织炎症的相关信号来实现。 相似文献
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TFEB links autophagy to lysosomal biogenesis 总被引：1，自引：0，他引：1
Settembre C Di Malta C Polito VA Garcia Arencibia M Vetrini F Erdin S Erdin SU Huynh T Medina D Colella P Sardiello M Rubinsztein DC Ballabio A 《Science (New York, N.Y.)》2011,332(6036):1429-1433
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McDonald PH Chow CW Miller WE Laporte SA Field ME Lin FT Davis RJ Lefkowitz RJ 《Science (New York, N.Y.)》2000,290(5496):1574-1577
beta-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of beta-arrestin 2 using a yeast two-hybrid screen and by coimmunoprecipitation from mouse brain extracts or cotransfected COS-7 cells. The upstream JNK activators apoptosis signal-regulating kinase 1 (ASK1) and mitogen-activated protein kinase (MAPK) kinase 4 were also found in complex with beta-arrestin 2. Cellular transfection of beta-arrestin 2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor activated JNK3 and triggered the colocalization of beta-arrestin 2 and active JNK3 to intracellular vesicles. Thus, beta-arrestin 2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a GPCR. 相似文献