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EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake

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CELL 1999年第5期96卷 677-687页

作者： Wilde, A Beattie, EC Lem, L Riethof, DA Liu, SH Mobley, WC Soriano, P Brodsky, FM Univ Calif San Francisco Dept Immunol & Microbiol GW Hooper Fdn San Francisco CA 94143 USA Univ Calif San Francisco Dept Biopharmaceut Sci San Francisco CA 94143 USA Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA Univ Calif San Francisco Dept Physiol San Francisco CA 94143 USA Univ Calif San Francisco Dept Neurol San Francisco CA 94143 USA Univ Calif San Francisco Dept Anat San Francisco CA 94143 USA Fred Hutchinson Canc Res Ctr Div Basic Sci Seattle WA 98109 USA

Epidermal growth factor (EGF) binding to its receptor causes rapid phosphorylation of the clathrin heavy chain at tyrosine 1477, which lies in a domain controlling clathrin assembly. EGF-mediated clathrin phosphorylation is followed by clathrin redistribution to the cell periphery and is the product of downstream activation of SRC kinase by EGF receptor (EGFR) signaling. In cells lacking SRC kinase, or cells treated with a specific SRC family kinase inhibitor, EGF stimulation of clathrin phosphorylation and redistribution does not occur, and EGF endocytosis is delayed. These observations demonstrate a role for SRC kinase in modification and recruitment of clathrin during ligand-induced EGFR endocytosis and thereby define a novel effector mechanism for regulation of endocytosis by receptor signaling.

关键词：氨基酸序列生物转运网格蛋白/代谢胞吞作用/药物作用表皮生长因子/代谢配体分子序列数据磷酰化/药物作用蛋白质加工转译后/药物作用原癌基因蛋白质pp60(c-src)/代谢受体表皮生长因子/生理学重组融合蛋白质类/代谢肿瘤细胞培养的 src族激酶类/代谢动物牛人类小鼠

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Role of arrestins in endocytosis and signaling of α₂-adrenergic receptor subtypes

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第16期274卷 11253-11259页

作者： DeGraff, JL Gagnon, AW Benovic, JL Orsini, MJ Thomas Jefferson Univ Kimmel Canc Inst Dept Microbiol & Immunol Philadelphia PA 19107 USA

We investigated the role of arrestins in the trafficking of human alpha(2)-adrenergic receptors (alpha(2)-ARs) and the effect of receptor trafficking on p42/p44 RAP kinase activation. alpha(2)-ARs expressed in COS-1 cells demonstrated a modest level of agonist-mediated internalization, with alpha(2c) > alpha(2b) > alpha(2a). However, upon coexpression of arrestin-2 (beta-arrestin-1) or arrestin-3 (beta-arrestin-2), internalization of the alpha(2b) AR was dramatically enhanced and redistribution of receptors to clathrin coated vesicles and endosomes was observed. Internalization of the alpha 2c AR was selectively promoted by coexpression of arrestin-3, while alpha 2a AR internalization was only slightly stimulated by coexpression of either arrestin. Coexpression of GRK2 had no effect on the internalization of any alpha 2-AR subtype, either in the presence or absence of arrestins. Internalization of the alpha 2b and alpha 2c ARs was inhibited by coexpression of dominant negative dynamin-K44A However, alpha 2-AR-mediated activation of either endogenous or cotransfected p42/p44 mitogen-activated protein (IMAP) kinase was not affected by either dynamin-K44A or arrestin-3. Moreover, activation of p42/ p44 MAP kinase by endogenous epidermal growth factor, lysophosphatidic acid, and beta(2)-adrenergic receptors was also unaltered by dynamin-K44A. In summary, our data suggest that internalization of the alpha(2b), alpha(2c), and to a lesser extent alpha(2a) ARs, is both arrestin- and dynamin de pendent. However, endocytosis does not appear to be required for alpha(2)-adrenergic, epidermal growth factor, lysophosphatidic acid, or beta(2)-adrenergic receptor-mediated p42/p44 MAP kinase activation in COS-1 cells.

关键词：氨基酸序列抑制蛋白类/生理学 COS细胞钙-钙调素依赖性蛋白激酶类/代谢胞吞作用/生理学酶激活表皮生长因子/生理学 GTP结合蛋白质类/代谢溶血磷脂素类/生理学显微镜检查荧光分子序列数据受体蛋白质酪氨酸激酶类/代谢受体肾上腺素能α2/生理学受体肾上腺素能β2/生理学信号传导/生理学动物人类

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Epidermal growth factor negatively regulates chondrogenesis of mesenchymal cells by modulating the protein kinase C-α, Erk-1, and p38 MAPK signaling pathways

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第16期275卷 12353-12359页

作者： Yoon, YM Oh, CD Kim, DY Lee, YS Park, JW Huh, TL Kang, SS Chun, JS Kyungpook Natl Univ Dept Biol Taegu 702701 South Korea Kyungpook Natl Univ Dept Biochem Taegu 702701 South Korea Kyungpook Natl Univ Dept Genet Engn Taegu 702701 South Korea

During limb development, epithelial cells in the apical ectodermal ridge keep the underlying mesenchymal cells in a proliferative state preventing differentiation by secreting signaling molecules such as epidermal growth factor (EGF). We investigated the molecular mechanism of the EGF effect on the regulation of micromass culture-induced chondrogenesis of chick limb bud mesenchymal cells as a model system. We found that expression and tyrosine phosphorylation of the EGF receptor was increased transiently during chondrogenesis, Exogenous EGF inhibited chondrogenic differentiation of mesenchymal cells, and this effect was reversed by the EGF receptor inhibitor AG1478, EGF treatment also inhibited the expression and activation of protein kinase C-alpha, whereas it activated Erk-1 and inhibited p38 mitogen-activated protein kinase, all of which appeared to be involved in the EGF-induced inhibition of chondrogenesis. Stimulation of the EGF receptor blocked precartilage condensation and altered the expression of cell adhesion molecules such as N-cadherin and integrins alpha(5) and beta(1), All these EGF effects were reversible by AG1478, The data indicate that EGF negatively regulate chondrogenesis of chick limb bud mesenchymal cells by inhibiting precartilage condensation and by modulating signaling pathways including those of protein kinase C-alpha, Erk-1, and p38 mitogen-activated protein kinase.

关键词：钙-钙调素依赖性蛋白激酶类/代谢细胞黏附细胞分裂细胞培养的软骨细胞/生理学酶激活表皮生长因子/生理学同工酶类/代谢中胚层/生理学丝裂原活化蛋白激酶3 丝裂原激活蛋白激酶类/代谢蛋白激酶C/代谢蛋白激酶Cα 信号传导 p38丝裂原活化蛋白激酶类动物鸡胚

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Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第7期275卷 5096-5103页

作者： Wu, LW Mayo, LD Dunbar, JD Kessler, KM Baerwald, MR Jaffe, EA Wang, DF Warren, RS Donner, DB Indiana Univ Sch Med Walther Oncol Ctr Indianapolis IN 46202 USA Indiana Univ Sch Med Dept Microbiol & Immunol Indianapolis IN 46202 USA Interfaith Med Ctr Dept Med Brooklyn NY 11238 USA Cornell Univ Med Ctr New York NY 10021 USA SUNY Hlth Sci Ctr Brooklyn NY 11203 USA Univ Calif San Francisco Dept Surg San Francisco CA 94143 USA

This study was initiated to identify signaling proteins used by the receptors for vascular endothelial cell growth factor KDR/FlK1, and Flt1, Two-hybrid cloning and immunoprecipitation from human umbilical vein endothelial cells (HUVEC) showed that KDR binds to and promotes the tyrosine phosphorylation of phospholipase C gamma (PLC gamma), Neither placental growth factor, which activates Flt1, epidermal growth factor (EGF), or fibroblast growth factor (FGF) induced tyrosine phosphorylation of PLC gamma, indicating that KDR is uniquely important to PLC gamma activation in HUVEC, By signaling through KDR, VEGF promoted the tyrosine phosphorylation of focal adhesion kinase, induced activation of Akt, protein kinase C epsilon (PKC epsilon), mitogen-activated protein kinase (MAPK), and promoted thymidine incorporation into DNA VEGF activates PLC gamma, PKC epsilon, and phosphatidylinositol 3-kinase independently of one another. MEK, PLC gamma, and to a lesser extent PKC, are in the pathway through which KDR activates MAPK. PLC gamma or PKC inhibitors did not affect FGF- or EGF-mediated MAPK activation. MAPK/ERK kinase inhibition diminished VEGF-, FGF-, and EGF-promoted thymidine incorporation into DNA, However, blockade of PKC diminished thymidine incorporation into DNA induced by VEGF but not FGF or EGF. Signaling through KDR/Flk1 activates signaling pathways not utilized by other mitogens to induce proliferation of HUVEC.

关键词：细胞黏附分子/代谢细胞分裂/生理学细胞培养的内皮生长因子/生理学内皮血管/细胞学内皮血管/酶学内皮血管/代谢酶激活表皮生长因子/生理学成纤维细胞生长因子/生理学黏着斑激酶1 黏着斑蛋白酪氨酸激酶类同工酶类/代谢淋巴因子/生理学有丝分裂原/生理学新生血管化生理性磷脂酶Cγ 蛋白激酶C/代谢蛋白激酶Cε 蛋白质丝氨酸苏氨酸激酶蛋白酪氨酸激酶类/代谢原癌基因蛋白质类/代谢原癌基因蛋白质c-akt 受体蛋白质酪氨酸激酶类/代谢受体生长因子/代谢受体血管内皮生长因子重组蛋白质类/代谢信号传导 C型磷脂酶类/代谢血管内皮生长因子A 血管内皮生长因子类人类

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Cyclooxygenase-2 expression inhibits trophic withdrawal apoptosis in nerve growth factor-differentiated PC12 cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第16期275卷 12095-12101页

作者： McGinty, A Chang, YWE Sorokin, A Bokemeyer, D Dunn, MJ Med Coll Wisconsin Dept Med Milwaukee WI 53226 USA Med Coll Wisconsin Cardiovasc Res Ctr Milwaukee WI 53226 USA Univ Bonn Med Poliklin D-53111 Bonn Germany

Cyclooxygenase-2 (Cox-2), an enzyme responsible for catalyzing the committed step in prostanoid biosynthesis, is the product of an immediate early gene capable of being up-regulated by diverse stimuli. Significantly Cox-2 mRNA is absent from rat pheochromocytoma (PC12) cells, both basally and following stimulation with a range of agonists, Using PC12 cells engineered to stably express isopropyl-1-thio-beta-D-galactopyranoside-inducible Cox-2 (PCXII-4), we have investigated the putative effects of Cox-2 expression on differentiation, proliferation, and trophic withdrawal apoptosis, Cox-2 bioactivity had no effect on nerve growth factor-induced differentiation, epidermal growth factor-induced proliferation, or aromatic L-amino acid decarboxylase expression, However, trophic withdrawal apoptosis, induced by the removal of nerve growth factor following differentiation, was markedly reduced in the PCXII-4 when compared with control cells, as assessed by annexin V staining, DNA laddering, and Hoechst 33258 staining. The specificity of this effect was confirmed using two pharmacologically distinct nonsteroidal antiinflammatory drugs, indomethacin and NS398. Investigations showed that the activity of the pro-apoptotic protease caspase-3 was reduced in PCXII cells. This study demonstrates that Cox-2-derived prostaglandins exert cytoprotective effects in trophic factor withdrawal apoptosis and provides evidence that this is, at least in part, due to suppression of caspase-3 activity.

关键词：细胞凋亡/生理学半胱氨酸天冬氨酸蛋白酶3 半胱氨酸天冬氨酸蛋白酶/代谢细胞分化环氧化酶2 酶诱导表皮生长因子/生理学同工酶类/生物合成同工酶类/遗传学异丙硫半乳糖苷/药理学神经生长因子类/生理学 PC12细胞前列腺素内过氧化物合酶类/生物合成前列腺素内过氧化物合酶类/遗传学 RNA 信使/代谢动物大鼠

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The internalization and endosomal trafficking of the EGF receptor in response to EGF is delayed in the waved-2 mouse liver

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第3期267卷 881-886页

作者： Keegan, BP Sheflin, LG Spaulding, SW VA Western New York Healthcare Syst Buffalo NY 14215 USA SUNY Buffalo Dept Physiol & Biophys Buffalo NY 14215 USA SUNY Buffalo Dept Med Buffalo NY 14215 USA

The EGF receptor in waved-2 mice contains a point mutation that renders it kinase deficient. We investigated how the waved-2 mutation affects the internalization and endosomal trafficking of the receptor in vivo in response to EGF. When the waved-a mice mere injected with EGF, there was similar to 50% less tyrosine phosphorylation detected in whole-liver homogenate compared to wild-type background mice. Although EGF increased the EGF receptor levels in the early and late liver endosomal fractions of waved-a mice, its trafficking was delayed compared to wild-type mice. Ubiquitination of the EGF receptor may affect its endosomal sorting. We found that a similar amount of ECF receptor was immunoprecipitated from the endosomal fractions of EGF-treated waved-a and wild-type with antiubiquitin antibody. These results demonstrate that the waved-2 EGF receptor can become ubiquitinated and can be trafficked to the late endosomes, although it appears that its kinase deficiency delays this process. (C) 2000 Academic Press.

关键词：交叉遗传内颗粒/生理学表皮生长因子/药理学杂合子纯合子动力学肝/药物作用肝/生理学肝/超微结构小鼠近交C57BL 小鼠突变型磷酸酪氨酸/代谢点突变受体表皮生长因子/药物作用受体表皮生长因子/遗传学受体表皮生长因子/生理学动物女(雌)性男(雄)性小鼠

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Regulation of porcine adipogenesis in vitro, as compared with other species

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DOMESTIC ANIMAL ENDOCRINOLOGY 1999年第2-3期17卷 257-267页

作者： Boone, C Grégoire, F Remacle, C Univ Catholique Louvain Fac Sci Biol Cellulaire Lab Unite Biol Anim B-1348 Louvain Belgium Parke Davis Lab Mol Genet Alameda CA 94505 USA

In vitro studies, mostly performed on murine cell lines, allowed us to identify the role played by hormonal agents, second-messenger pathways, extracellular matrix proteins, and transcription factors in adipose conversion. Some information has also been reported when studies were conducted on primary cultures that originated from various species. However, because of conflicting results, probably caused, at least in part, by species specificity, developing cultures of preadipose cells from economically important species appeared necessary to better understand and control the animals' fat development. We reviewed our current knowledge concerning the regulation of cultured porcine preadipose cells by hormones, second-messenger pathways, and extracellular matrix proteins. The results clearly demonstrate that such primary cultures are essential to avoid the establishment of hazardous concepts originated from rodent and aneuploid cell lines in particular. (C) 1999 Elsevier Science Inc. All rights reserved.

关键词：脂细胞/细胞学脂细胞/生理学脂肪组织/细胞学脂肪组织/生理学细胞分化细胞培养的环AMP/生理学表皮生长因子/生理学细胞外基质蛋白质类/生理学生长激素/生理学胰岛素/生理学胰岛素样生长因子Ⅰ/生理学蛋白激酶C/生理学猪/生理学三碘甲状腺原氨酸/生理学动物人类小鼠兔大鼠

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Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第11期96卷 6235-6240页

作者： Dong, JY Opresko, LK Dempsey, PJ Lauffenburger, DA Coffey, RJ Wiley, HS Univ Utah Dept Pathol Salt Lake City UT 84132 USA Vanderbilt Univ Dept Med Nashville TN 37232 USA Vet Affairs Med Ctr Nashville TN 37232 USA MIT Div Bioengn & Environm Hlth Cambridge MA 02139 USA MIT Canc Res Ctr Cambridge MA 02139 USA

Ligands that activate the epidermal growth factor receptor (EGFR) are synthesized as membrane-anchored precursors that appear to be proteolytically released by members of the ADAM family of metalloproteases. Because membrane-anchored EGFR ligands are thought to be biologically active, the role of ligand release in the regulation of EGFR signaling is unclear. To investigate this question, we used metalloprotease inhibitors to block EGFR ligand release from human mammary epithelial cells. These cells express both transforming growth factor a and amphiregulin and require autocrine signaling through the EGFR for proliferation and migration. We found that metalloprotease inhibitors reduced cell proliferation in direct proportion to their effect on transforming growth factor a release. Metalloprotease inhibitors also reduced growth of EGF-responsive tumorigenic cell lines and were synergistic with the inhibitory effects of antagonistic EGFR antibodies. Blocking release of EGFR ligands also strongly inhibited autocrine activation of the EGFR and reduced both the rate and persistence of cell migration. The effects of metalloprotease inhibitors could be reversed by either adding exogenous EGF or by expressing an artificial gene for EGF that lacked a membrane-anchoring domain. Our results indicate that soluble rather than mem brane-anchored forms of the ligands mediate most of the biological effects of EGFR ligands. Metalloprotease inhibitors have shown promise in preventing spread of metastatic disease. Many of their antimetastatic effects could be the result of their ability to inhibit autocrine signaling through the EGFR.

关键词：抗体单克隆/药理学细胞分裂/药物作用细胞系细胞运动/药物作用表皮生长因子/遗传学表皮生长因子/药理学表皮生长因子/生理学上皮细胞/细胞学上皮细胞/药物作用上皮细胞/生理学羟肟酸类/药理学配体金属内肽酶类/代谢磷酰化蛋白酶抑制药/药理学信号传导转录遗传转化生长因子α/生物合成人类

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Mathematical modelling of juxtacrine patterning

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BULLETIN OF MATHEMATICAL BIOLOGY 2000年第2期62卷 293-320页

作者： Wearing, HJ Owen, MR Sherratt, JA Heriot Watt Univ Dept Math Edinburgh EH14 4AS Midlothian Scotland Univ Utah Dept Math Salt Lake City UT 84112 USA

Spatial pattern formation is one of the key issues in developmental biology. Some patterns arising in early development have a very small spatial scale and a natural explanation is that they arise by direct cell-cell signalling in epithelia. This necessitates the use of a spatially discrete model, in contrast to the continuum-based approach of the widely studied Turing and mechanochemical models. In this work, we consider the pattern-forming potential of a model for juxtacrine communication, in which signalling molecules anchored in the cell membrane bind to and activate receptors on the surface of immediately neighbouring cells. The key assumption is that ligand and receptor production are both up-regulated by binding. By linear analysis, we show that conditions for pattern formation are dependent on the feed back functions of the model. We investigate the form of the pattern: specifically, we look at how the range of unstable wavenumbers varies with the parameter regime and find an estimate for the wavenumber associated with the fastest growing mode. A previous juxtacrine model for Delta-Notch signalling studied by Collier er nl. (1996, J. Theor: Biol. 183, 429-446) only gives rise to patterning with a length scale of one or two cells, consistent with the fine-grained patterns seen in a number of developmental processes. However, there is evidence of longer range patterns in early development of the fruit fly Drosophila. The analysis we carry out predicts that patterns longer than one or two cell lengths are possible with our positive feedback mechanism, and numerical simulations confirm this. Our work shows that juxtacrine signalling provides a novel and robust mechanism for the generation of spatial patterns. (C) 2000 Society for Mathematical Biology.

关键词：躯体发育模式/生理学细胞间通讯/生理学计算机模拟果蝇属/生长和发育果蝇属/生理学反馈线性模型模型生物学受体表皮生长因子/生理学转化生长因子α/生理学动物

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Growth factors: Importance in wound healing and maintenance of transparency of the cornea

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PROGRESS IN RETINAL AND EYE RESEARCH 2000年第1期19卷 113-129页

作者： Imanishi, J Kamiyama, K Iguchi, I Kita, M Sotozono, C Kinoshita, S Kyoto Prefectural Univ Med Dept Microbiol Kamikyo Ku Kyoto 6028566 Japan Kyoto Prefectural Univ Med Dept Ophthalmol Kamikyo Ku Kyoto 6028566 Japan

The mechanism of corneal wound healing has not been clarified yet. However, evidence has accumulated that various kinds of growth factor such as epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF). keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF) play a key role in corneal wound healing. For example, these growth factors are expressed in the corneal epithelial cells. keratocytes and endothelial cells, and their receptors are expressed in the corneal cells. Furthermore. these growth factors promote the proliferation of corneal cells and induce the migration of corneal cells. In addition to the growth factors. inflammatory cytokines such as interleukin (IL)1. IL-6 and TNF-alpha are involved in corneal wound healing. These cytokines are expressed in the normal and inflammatory cornea after infections, alkali-burn. etc. where they control the growth of corneal cells and induce the migration of corneal cells. Thus. a number of growth factors and cytokines function in the regulation of corneal cell proliferation and in the maintenance of corneal transparency. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：细胞运动/生理学角膜/损伤细胞因子类/生理学表皮生长因子/生理学生长物质/遗传学生长物质/生理学血小板源性生长因子/生理学转化生长因子β/生理学伤口愈合/生理学动物人类

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