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中华眼底病杂志 2010年第3期26卷 223-226页

作者：杜玮邓爱军潍坊医学院附属医院眼科 261402

目的观察ephrin A家族的基因是否参与氧诱导的小鼠视网膜新生血管（RNV）形成.方法利用氧诱导新生小鼠C57BL/6J制备氧诱RNV模型,用逆转录聚合酶链式反应（RT-PCT）检测ephrin A1～A5在模型组小鼠视网膜和同龄正常小鼠（对照组）视网... 详细信息

目的观察ephrin A家族的基因是否参与氧诱导的小鼠视网膜新生血管（RNV）形成.方法利用氧诱导新生小鼠C57BL/6J制备氧诱RNV模型,用逆转录聚合酶链式反应（RT-PCT）检测ephrin A1～A5在模型组小鼠视网膜和同龄正常小鼠（对照组）视网膜中的表达.结果 ephrin A1～A5mRNA均在正常视网膜发育的某一阶段或者发育的全程表达.在模型组小鼠视网膜中,ephrin A1 mRNA的表达量相对于对照组小鼠明显上调（t=3.19,P=0.019）;ephrin A2 mRNA的表达量在15日龄的模型组小鼠中相对于对照组小鼠显著上调（t=3.71,P=0.033）;ephrin A3～A5 mRNA在12、13日龄的模型组小鼠视网膜中相对于对照组小鼠表达下调或者缺失,而在15日龄的模型组小鼠视网膜相对于对照组小鼠视网膜显著上调（t=3.785,P=0.002）.结论 ephrin A家族的基因参与视网膜的发育和视网膜病理性血管生成等重要的生理和病理过程.

关键词：视网膜新生血管化/病理生理学蛋白酪氨酸激酶类/生理学动物实验

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Therapeutic consequences of pathology and prognostic factors in aggressive NHL - Analysis of ALCL

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ANNALS OF HEMATOLOGY 2001年第3-Sup期80卷 B45-B48页

作者： Gascoyne, RD A1. Department of Pathology Britisch Columbia Cancer Agency e-mail: rgascoyne@bccancer.hc.ca Fax: 001/604/877-6178 CA

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β-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC -: Role of β-arrestin1-dependent targeting of c-SRC in receptor endocytosis

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第15期275卷 11312-11319页

作者： Miller, WE Maudsley, S Ahn, S Khan, KD Luttrell, LM Lefkowitz, RJ Duke Univ Med Ctr Howard Hughes Med Inst Dept Med Durham NC 27710 USA Duke Univ Med Ctr Howard Hughes Med Inst Dept Biochem Durham NC 27710 USA

beta-Arrestins can act as adapter molecules, coupling G-protein-coupled receptors to proteins involved in mitogenic as well as endocytic pathways. We have previously identified c-SRC as a molecule that is rapidly recruited to the beta 2-adrenergic receptor in a beta-arrestin1-dependent manner, Recruitment of c-SRC to the receptor appears to be involved in pathways leading to receptor internalization and mitogen-activated protein kinase activation. This recruitment of c-SRC to the receptor involves an interaction between the amino-terminal proline-rich region of beta-arrestin1 and the Src homology 3 (SH3) domain of c-SRC, but deletion of the proline-rich domain does not totally ablate the interaction. We have found that a major interaction also exists between beta-arrestin1 and the catalytic or kinase domain (SH1) of c-SRC, We therefore hypothesized that a catalytically inactive mutant of the isolated catalytic subunit, SH1 (kinase dead) (SH1(KD)), would specifically block those cellular actions of c-SRC that are mediated by beta-arrestin1 recruitment to the G-protein-coupled receptor. In contrast, the majority of cellular phosphorylations catalyzed by c-SRC, which do not involve interaction with the SH1 domain, would be predicted to be unaffected. The SH1(KD) mutant did indeed block beta 2-adrenergic receptor internalization and receptor-stimulated tyrosine phosphorylation of dynamin, actions previously shown to be c-SRC-dependent, In contrast, SAM-68 and whole cell tyrosine phosphorylation by c-SRC was unaffected, indicating that the SH1(KD) mutant did not inhibit c-SRC tyrosine kinase activity in general. These results not only clarify the nature of the beta-arrestin1/c-SRC interaction but also implicate beta-arrestin1 as an important mediator of receptor internalization by recruiting tyrosine kinase activity to the cell surface to phosphorylate key endocytic intermediates, such as dynamin.

关键词：抑制蛋白类/生理学催化域细胞系动力蛋白质类胞吞作用 GTP磷酸水解酶类/代谢磷酰化蛋白酪氨酸激酶类/化学蛋白酪氨酸激酶类/生理学受体肾上腺素能β2/代谢构效关系酪氨酸/代谢 src同源域 src族激酶类人类

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Phosphorylation of paxillin via the ERK mitogen-activated protein kinase cascade in EL4 thymoma cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第15期275卷 11333-11340页

作者： Ku, H Meier, KE Med Univ S Carolina Dept Cell & Mol Pharmacol Charleston SC 29425 USA

Intracellular signals can regulate cell adhesion via several mechanisms in a process referred to as "inside-out" signaling In phorbol ester-sensitive EL4 thymoma cells, phorbol-la-myristate 13-acetate (PMA) induces activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases and promotes cell adhesion. In this study, clonal EL4 cell lines with varying abilities to activate ERKs in response to PIMA were used to examine signaling events occurring downstream of ERK activation. Paxillin, a multifunctional docking protein involved in cell adhesion, was phosphorylated on serine/threonine residues in response to PMA treatment. This response was correlated with the extent and time course of ERK activation. PMA-induced phosphorylation of paxillin was inhibited by compounds that block the ERK activation pathway in EL4 cells, primary murine thymocytes, and primary murine splenocytes. Paxillin was phosphorylated in vitro by purified active ERK2. Two-dimensional electrophoresis revealed that PMA treatment generated a complex pattern of phosphorylated paxillin species in intact cells, some of which were generated by ERR-mediated phosphorylation in vitro. An ERK pathway inhibitor interfered with PMA-induced adhesion of sensitive EL4 cells to substrate. These findings describe a novel inside-out signaling pathway by which the ERK cascade may regulate events involved in adhesion.

关键词：细胞黏附/药物作用细胞支架蛋白质类/代谢丝裂原激活蛋白激酶类/生理学桩蛋白磷蛋白类/代谢磷酰化蛋白质酪氨酸磷酸酶类/生理学蛋白酪氨酸激酶类/生理学 T淋巴细胞/代谢十四酰佛波乙酯/药理学胸腺瘤/代谢胸腺瘤/病理学肿瘤细胞培养的动物小鼠

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Hck enhances the adherence of lipopolysaccharide-stimulated macrophages via Cbl and phosphatidylinositol 3-kinase

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第19期275卷 14615-14623页

作者： Scholz, G Cartledge, K Dunn, AR Royal Melbourne Hosp Ludwig Inst Canc Res Mol Biol Lab Melbourne Vic 3050 Australia

Src family tyrosine kinases have previously been proposed to mediate some of the biological effects of lipopolysaccharide on macrophages, Accordingly, we have sought to identify substrates of Src family kinases in lipopolysaccharide-stimulated macrophages. Stimulation of Bac1.2F5 macrophage cells with lipopolysaccharide was found to induce gradual and persistent tyrosine phosphorylation of Cbl in an Src family kinase-dependent manner. Immunoprecipitation experiments revealed that Cbl associates with Hck in Bac1.2F5 cells, while expression of an activated form of Hck in Bac1.2F5 cells induces tyrosine phosphorylation of Cbl in the absence of lipopolysaccharide stimulation. The Src homology 3 domain of Hck can directly bind Cbl, and this interaction is important for phosphorylation of Chi. Association of the p85 subunit of phosphatidylinositol (PI) 3-kinase with Cbl is enhanced following lipopolysaccharide stimulation of Bac1.2F5 cells, and transient expression experiments indicate that phosphorylation of Cbl by Hck can facilitate the association of p85 with Cbl, Lipopolysaccharide treatment also stimulates the partial translocation of lick to the cytoskeleton of Bac1.2F5 cells. Notably, lipopolysaccharide enhances the adherence of Bac1.2F5 cells, an effect that is dependent on the activity of Src family kinases and PI 3-kinase. Thus, we postulate that Hck enhances the adherence of lipopolysaccharide-stimulated macrophages, at least in part, via Cbl and PI 3-kinase.

关键词：生物转运细胞黏附/生理学细胞系细胞骨架/代谢脂多糖类/药理学巨噬细胞活化/药物作用巨噬细胞/细胞学巨噬细胞/药物作用巨噬细胞/酶学巨噬细胞/代谢磷酸肌醇3-激酶类/代谢磷酰化蛋白酪氨酸激酶类/生理学原癌基因蛋白质类/代谢原癌基因蛋白质类/生理学原癌基因蛋白质c-cbl 原癌基因蛋白质c-hck 泛素蛋白连接酶类 src同源域

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Transcription factors Ets1, NF-κB, and Sp1 are major determinants of the promoter activity of the human protein kinase CK2α gene

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第24期275卷 18327-18336页

作者： Krehan, A Ansuini, H Böcher, O Grein, S Wirkner, U Pyerin, W Deutsch Krebsforschungszentrum Biochem Zellphysiol B0200 D-69120 Heidelberg Germany Univ Perugia I-06100 Perugia Italy

CK2 alpha is one of two isoforms of protein kinase CK2, a highly conserved, ubiquitous, and vital phosphotransferase whose expression is kept at constant cellular levels and whose dysregulated expression has been linked to malignant diseases. The upstream sequence of the gene coding for human CK2 alpha (CSNK1A1, chromosomal location 20p13) has been examined for promoter location and transcription factor interactions using reporter gene assays (luciferase;HeLa cells), site-directed mutagenesis, electrophoretic mobility shift assays, super-shifts, UV cross-linking, Western blotting, and DNA affinity chromatography. Highest promoter activity has been found in a region comprising positions -9 to 46, Factors Spl, Ets-1, and NF-kappa B have been identified as interaction partners and, by mutation of individual sites and simultaneous mutations of two or more sites, shown to cross-talk to each other. At least two of the factors (Spl;NF-kappa B) were susceptible to phosphorylation by CK2 holoenzyme, a tetramer: composed of two CK2 alpha and two regulatory CK2 beta proteins, but not by individual CK2 alpha, Because the phosphorylation decreases promoter binding and repeated immunoprecipitation reveals presence of "free" CK2 beta in cell extracts, it is tempting to speculate that the gene product CK2 alpha might readily form CK2 holoenzyme and feed back onto gene transcription. The data represent the first promoter control analysis of a mammalian CK2 alpha gene and provide a hypothesis of how the constant expression level of CK2 alpha may be achieved.

关键词：酪蛋白激酶Ⅱ 色谱法亲和 DNA结合蛋白质类/遗传学基因表达调控酶学诱变定点 NF-κB/生理学磷酰化启动区(遗传学) 蛋白质结合蛋白质丝氨酸苏氨酸激酶/遗传学蛋白酪氨酸激酶类/生理学原癌基因蛋白质c-ets-1 原癌基因蛋白质类/生理学原癌基因蛋白质c-ets Sp1转录因子/生理学转录因子/生理学人类

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Characterization of the tyrosine kinases RAFTK/Pyk2 and FAK in nerve growth factor-induced neuronal differentiation

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第26期275卷 19768-19777页

作者： Park, SY Avraham, H Avraham, S Harvard Univ Sch Med Beth Israel Deaconess Med Ctr Harvard Inst MedDiv Expt Med Boston MA 02115 USA

The related adhesion focal tyrosine kinase (RAFTK), a member of the focal adhesion kinase (FAK) family and highly expressed in brain, is a key mediator of various extracellular signals that elevate intracellular Ca2+ concentration. We investigated RAFTK and FAK signaling upon nerve growth factor (NGF) stimulation of PC12 cells. NGF induced the tyrosine phosphorylation of RAFTK in a time- and dose-dependent manner, whereas no change in the tyrosine phosphorylation of FAK was observed Chemical inhibition showed that RAFTK phosphorylation was inhibited by blocking phospholipase Cy activity or intracellular Ca2+. Blocking of extracellular Ca2+ or phosphatidylinositol 3-kinase activity partially reduced the phosphorylation of RAFTK. In addition, disruption of actin polymerization abolished RAFTK phosphorylation, indicating that an intact actin-based cytoskeletal organization is required for RAFTK phosphorylation. The focal adhesion molecule paxillin was co-immunoprecipitated with RAFTK, and its tyrosine phosphorylation was increased in a Ca2+-dependent manner upon NGF stimulation. Confocal microscopic analysis demonstrated that RAFTK translocated from the cytoplasm to potential neurite initiation sites at the cell periphery, where RAFTK co-localized with paxillin and bundled actin in the early phase (within 5 min) of NGF stimulation, whereas FAK co-localized with paxillin at "point contacts," which are the primary cell adhesion sites in neuronal cells. Significant distribution of RAFTK was observed in the neurites and growth cones of differentiated PC12 cells. Furthermore, potassium depolarization induced the tyrosine phosphorylation of both RAFTK and paxillin in an intracellular Ca2+ dependent manner in the differentiated PC12 cells. Taken together, these results demonstrate that RAFTK is involved in NGF-induced cytoskeletal organization and may play a role in neurite and growth cone function(s).

关键词：肌动蛋白类/代谢钙/代谢载体蛋白质类/代谢细胞黏附细胞分化/生理学细胞膜/代谢培养基无血清/代谢细胞质/代谢细胞支架蛋白质类/代谢细胞骨架/代谢 DNA 互补/代谢剂量效应关系药物酶抑制剂/药理学黏着斑激酶1 黏着斑激酶2 黏着斑蛋白酪氨酸激酶类同工酶类/代谢膜蛋白质类/代谢模型生物学神经生长因子/代谢神经元/代谢 PC12细胞桩蛋白磷脂酶Cγ 磷蛋白类/代谢磷酰化/药物作用蛋白酪氨酸激酶类/化学蛋白酪氨酸激酶类/代谢蛋白酪氨酸激酶类/生理学受体 trkA 时间因素转染 C型磷脂酶类/代谢酪氨酸/代谢动物大鼠

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第37期275卷 29153-29161页

作者： Annerén, C Reedquist, KA Bos, JL Welsh, M Uppsala Univ Biomedicum Dept Med Cell Biol S-75123 Uppsala Sweden Univ Utrecht Physiol Chem Lab NL-3584 CG Utrecht Netherlands Univ Utrecht Ctr Biomed Genet NL-3584 CG Utrecht Netherlands

The rat pheochromocytoma cell line PC12 is extensively used as a model for studies of neuronal cell differentiation. These cells develop a sympathetic neuronlike phenotype when cultured in the presence of nerve growth factor. The present study was performed in or der to assess the role of mouse GTK (previously named BSK/IYK), a cytoplasmic tyrosine kinase belonging to the Src family, for neurite outgrowth in PC12 cells. We report that PC12 cells stably overexpressing GTK exhibit a larger fraction of cells with neurites as compared with control cells, and this response is not accompanied by an increased ERK activity. Treatment of the cells with the MEK inhibitor PD98059 did not reduce the GTK-dependent increased in neurite outgrowth. GTK expression induces a nerve growth factor-independent Rap1 activation, probably through altered CrkII signaling. We observe increased CrkII complex formation with p130(Cas), focal adhesion kinase (FAK), and Shb in PC12-GTK cells. The expression of GTK also correlates with a markedly increased content of FAK, phosphorylation of the adaptor protein Shb, and an association between these two proteins. Transient transfection of GTK-over-expressing cells with RalGDS-RBD or Rap1GAP, inhibitors of the Rap1 pathway, reduces the GTK-dependent neurite outgrowth. These data suggest that GTK participates in a signaling pathway, perhaps involving Shb, FAK and Rap1, that induces neurite outgrowth in PC12 cells.

关键词：衔接蛋白质类信号转导载体蛋白质类/代谢黏着斑激酶1 黏着斑蛋白酪氨酸激酶类膜蛋白质类/代谢肿瘤蛋白质类神经生长因子/药理学神经突/生理学 PC12细胞磷酰化蛋白激酶类/代谢蛋白酪氨酸激酶类/生理学原癌基因蛋白质类/代谢原癌基因蛋白质c-crk 受体 trkA 酪氨酸/代谢 rap1GTP结合蛋白质类/生理学 src同源域 src族激酶类动物大鼠

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Cell communication: The inside story

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SCIENTIFIC AMERICAN 2000年第6期282卷 72-79页

作者： Scott, JN Pawson, T Howard Hughes Med Inst Coconut Grove FL 33133 USA Oregon Hlth Sci Univ Vollum Inst Portland OR 97201 USA Mt Sinai Hosp Samuel Lunenfeld Res Inst Program Mol Biol & Canc Toronto ON M5G 1X5 Canada Univ Toronto Toronto ON Canada

The tiny cells in our bodies harbor amazing internal communication networks. Understanding how those circuits are organized could help scientists develop new therapies for many serious disorders.

关键词：细胞间通讯/生理学模型分子蛋白酪氨酸激酶类/生理学信号传导/生理学 src同源域动物人类

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Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第43期275卷 33937-33944页

作者： Yamauchi, T Yamauchi, N Ueki, K Sugiyama, T Waki, H Miki, H Tobe, K Matsuda, S Tsushima, T Yamamoto, T Fujita, T Taketani, Y Fukayama, M Kimura, S Yazaki, Y Nagai, R Kadowaki, T Univ Tokyo Grad Sch Med Dept Internal Med Bunkyo Ku Tokyo 113 Japan Univ Tokyo Grad Sch Med Dept Pathol Tokyo 113 Japan Nagoya Univ Sch Med Dept Mol Pathogenesis Nagoya Aichi 466 Japan Tokyo Womens Med Coll Dept Internal Med 2 Tokyo 162 Japan Univ Tokyo Inst Med Sci Dept Oncol Tokyo 108 Japan Univ Tokyo Grad Sch Med Dept Obstet & Gynecol Tokyo 113 Japan Int Med Ctr Japan Tokyo 162 Japan

Overexpression of the oncogene for ErbB-2 is an unfavorable prognostic marker in human breast cancer. Its oncogenic potential appears to depend on the state of tyrosine phosphorylation, However, the mechanisms by which ErbB-2 is constitutively tyrosine-phospholylated in human breast cancer are poorly understood. We now show that human breast carcinoma samples with ErbB-2 overexpression have higher proliferative and metastatic activity in the presence of autocrine secretion of prolactin (PRL). By using a neutralizing antibody or dominant negative (DN) strategies or specific inhibitors, we also show that activation of Janus kinase Jak2 by autocrine secretion of PRL is one of the significant components of constitutive tyrosine phosphorylation of ErbB-2, its association with Grb2 and activation of mitogen-activated protein (MAP) kinase in human breast cancer cell lines that overexpress ErbB-2. Furthermore, the neutralizing anti-PRL antibody or erbB-2 antisense oligonucleotide or DN Jak2 or Jak2 inhibitor or DNRas or MAP kinase kinase inhibitor inhibits the proliferation of both untreated and PRL treated cells. Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. The identification of this novel cross-talk between ErbB-2 and the autocrine growth stimulatory loop for PRL may provide new targets for therapeutic and preventive intervention of human breast cancer.

关键词：衔接蛋白质类信号转导乳腺肿瘤/代谢乳腺肿瘤/病理学乳腺肿瘤/治疗细胞分裂 GRB2衔接蛋白质 Janus激酶2 MAP激酶信号系统丝裂原激活蛋白激酶类/生理学肿瘤转移磷酰化催乳素/生理学催乳素/分泌蛋白酪氨酸激酶类/生理学蛋白质类/生理学原癌基因蛋白质类受体 erbB-2/代谢酪氨酸/代谢女(雌)性人类

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