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Stimulation of protein kinase C modulates insulin-like growth factor-1-induced Akt activation in PC12 cells

JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第18期275卷 13377-13385页

作者： Zheng, WH Kar, S Quirion, R McGill Univ Dept Psychiat Douglas Hosp Res Ctr Verdun PQ H4H 1R3 Canada McGill Univ Dept Pharmacol & Therapeut Douglas Hosp Res Ctr Verdun PQ H4H 1R3 Canada

Activation of protein kinase C (PKC) plays an important role in the negative regulation of receptor signaling, but its effect on insulin-like growth factor-1 (IGF-1) receptor signaling remains unclear. In this study, we characterized the intracellular pathways involved in IGF-1-induced activation of Akt and evaluated the effects of the PKC activator phorbol 12-myristate 13-acetate (PMA) on the Akt activation by IGF-1. IGF-1 induced a time- and concentration-dependent activation of Akt. The effect of IGF-1 was blocked by the phosphatidylinositide 3-kinase (PI3K) inhibitors LY294002 (50 mu M) and wortmannin (0.5 mu M), but not by the MEK inhibitor PD98059 (50 mu M) or the p70 S6 kinase pathway inhibitor rapamycin (50 nM), suggesting that the stimulation of Akt by IGF-1 is mediated by the PI3K pathway. Interestingly, cotreatment with PIMA (400 nM) attenuated IGF-1-induced activation of Akt. The attenuation was blocked completely by the PKC inhibitor GO6983 (0.5 mu M), but only partially by the MEK inhibitor PD98059 (50 mu M), indicating that MAPK-dependent and -independent pathways are involved. PMA induced the activation of PKC in PC12 cells, and this induction was blocked by GO6983. These data further support the role of PKC in the effect of PMA. Moreover, PKC delta is likely involved in the action of PMA on the basis of data obtained using isoform-specific inhibitors such as rottlerin. PMA also decreased IGF-1-induced tyrosine phosphorylation of insulin receptor substrate-1 and its association with PI3K. Taken together, these results suggest, for the first time, that stimulation of PKC modulates IGF-1-induced activation of Akt.

关键词：酶激活/药物作用胰岛素样生长因子ⅰ/药理学 MAP激酶信号系统 PC12细胞蛋白激酶C/代谢蛋白质丝氨酸苏氨酸激酶/代谢信号传导/药物作用动物大鼠

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Mechanism of STAT3 activation by insulin-like growth factor I receptor

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第20期275卷 15099-15105页

作者： Zong, CS Chan, J Levy, DE Horvath, C Sadowski, HB Wang, LH CUNY Mt Sinai Sch Med Dept Microbiol New York NY 10029 USA CUNY Mt Sinai Sch Med Dept Immunobiol New York NY 10029 USA CUNY Mt Sinai Sch Med Dept Biochem & Mol Biol New York NY 10029 USA NYU Dept Pathol New York NY 10016 USA

Recent evidence indicates that STAT proteins can be activated by a variety of receptor and non-receptor protein-tyrosine kinases, Unlike cytokine-induced activation of STATs, where JAKs are known to play a pivotal role in phosphorylating STATs, the mechanism for receptor protein-tyrosine kinase-mediated activation of STATs remains elusive. In this study, we investigated the activation of STAT proteins by the insulin-like growth factor I receptor (IGF-IR) in vitro and in vivo and assessed the role of JAKs in the process of activation. We found that STAT3, but not STAT5, was activated in response to IGF-I in 293T cells cotransfected with IGF-IR and STAT expression vectors. Moreover, tyrosine phosphorylation of STATS, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector. Supporting the observation in 293T cells, endogenous STATS was tyrosine-phosphorylated upon IGF-I stimulation in the muscle cell line C2C12 as well as in various embryonic and adult mouse organs during different stages of development. Dominant-negative JAK1 or JAK2 was able to block the IGF-IR-mediated tyrosine phosphorylation of STATS in 293T cells. A newly identified family of proteins called SOCS (suppressor of cytokine signaling), including SOCS1, SOCS2, SOCS3 and CIS, was able to inhibit the IGF-I-induced STATS activation as well with varying degrees of potency, in which SOCS1 and SOCS3 appeared to have the higher inhibitory ability. Inhibition of STAT3 activation by SOCS could be overcome by overexpression of native JAK1 and JAK2. We conclude that IGF-I/IGF-IR is able to mediate activation of STATS in vitro and in vivo and that JAKs are essential for the process of activation.

关键词：细胞系 DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢胚胎哺乳动物胰岛素样生长因子ⅰ/药理学 Janus激酶1 Janus激酶2 肌骨骼磷酰化磷酸酪氨酸/代谢蛋白酪氨酸激酶类/代谢原癌基因蛋白质类受体 IGF1型/遗传学受体 IGF1型/生理学重组蛋白质类/代谢 STAT3转录因子反式激活因子类/遗传学反式激活因子类/代谢转染动物人类小鼠

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Distinct phosphatidylinositol 3-kinase lipid products accumulate upon oxidative and osmotic stress and lead to different cellular responses

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第50期274卷 35963-35968页

作者： Van der Kaay, J Beck, M Gray, A Downes, CP Univ Dundee Dept Biochem Dundee DD1 5EH Scotland Free Univ Berlin Inst Biochem D-14195 Berlin Germany Inst Med Sci Div Signal Transduct Therapy Dundee DD1 5EH Scotland

Signaling by phosphatidylinositol (PI) 3-kinases is mediated by S-phosphoinositides, which bind to Pleckstrin homology (PH) domains that are present in a wide spectrum of proteins. PH domains can be classified into three groups based on their different lipid binding specificities. Distinct 3-phosphoinositides can accumulate upon PI 3-kinase activation in cells in response to different stimuli and mediate specific cellular responses. In Swiss 3T3 mouse fibroblasts, oxidative stress induced by I mM H2O2 caused almost exclusive accumulation of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P-2), whereas osmotic stress increased both phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P-3) and PtdIns(3,4)P-2 levels. The increase in PtdIns(3,4)P-2 levels, caused by oxidative stress, correlated with the activation of protein kinase B, which has a promiscuous PH domain that binds both PtdIns(3,4,5)P-3 and PtdIns(3,4)P-2. p70 S6 kinase, another signaling component downstream of PI 3-kinase, however, was not activated by this oxidative stress-induced increase in PtdIns(3,4)P-2 levels. Increased PtdIns(3,4,5)P-3 and PtdIns(3,4)P-2 levels in response to osmotic stress did not correlate with protein kinase B activation, because of concomitant activation of an inhibitory pathway, but p70 S6 kinase was activated by osmotic stress. These results demonstrate that PtdIns(3,4)P-2 can accumulate independently of PtdIns(3,4,5)P-3 and exerts a pattern of cellular responses that is distinct from that induced by accumulation of PtdIns(3,4,5)P-3.

关键词： 3T3细胞酶激活过氧化氢/药理学胰岛素样生长因子ⅰ/药理学容积渗克分子浓度氧化还原氧化性应激磷酸肌醇3-激酶类/代谢磷脂酰肌醇磷酸盐类/代谢磷脂酰肌醇类/代谢蛋白质丝氨酸苏氨酸激酶原癌基因蛋白质类/代谢原癌基因蛋白质c-akt 核糖体蛋白质S6激酶类/代谢动物小鼠

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IGF-I promotes peripheral nervous system myelination

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CHARCOT-MARIE-TOOTH DISORDERS 1999年第1期883卷 124-130页

作者： Cheng, HL Russell, JW Feldman, EL Univ Michigan Dept Neurol Ann Arbor MI 48109 USA Univ Michigan Vet Adm Med Ctr Ann Arbor MI 48109 USA

Insulin-like growth factor-I (IGF-I) promotes the proliferation and differentiation of Schwann cells (SC), We use SC/dorsal root ganglion neuron (DRG) cocultures to examine the effects of IGF-I on the interaction between axons and SC. As SC extend processes toward the axon in the presence of IGF-I, these processes attach to and ensheath axons. Continued IGF-I exposure leads to enhanced P-0 expression and long-term myelination. No myelination occurs in the absence of IGF I. These data imply that IGF-I is critical not only for SC attachment and ensheathment of axone but also for long-term myelination.

关键词：动物新生细胞分裂/药物作用细胞培养的共同培养技术神经节脊/细胞学神经节脊/药物作用神经节脊/生理学胰岛素样生长因子ⅰ/药理学髓磷脂P0蛋白质/生物合成髓磷脂P0蛋白质/遗传学髓鞘/药物作用髓鞘/生理学髓鞘/超微结构神经元/细胞学神经元/生理学周围神经/细胞学周围神经/生理学大鼠 Sprague-Dawley 许旺细胞/细胞学许旺细胞/药物作用许旺细胞/生理学动物大鼠

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Potentiation of neuronal L calcium channels by IGF-1 requires phosphorylation of the α1 subunit on a specific tyrosine residue

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NEURON 2000年第1期27卷 121-131页

作者： Bence-Hanulec, KK Marshall, J Blair, LAC Brown Univ Dept Mol Pharmacol Physiol & Biotechnol Providence RI 02912 USA Cornell Univ Weill Med Coll Dept Physiol & Biophys New York NY 10021 USA

Insulin-like growth factor 1 (IGF-1) rapidly potentiates N and L calcium channel currents in cerebellar granule neurons by an unknown mechanism. Here, we show that the L channel alpha 1C subunit is tyrosine phosphorylated in response to IGF-1. Moreover, expression of kinase-dead c-Src in neurons or acute block of Src family kinases with a cell-permeable inhibitor specifically blocks L channel potentiation. Purified Src kinase phosphorylates tyrosine residue Y2122 of the C terminus of neuronal alpha 1C in vitro, and c- and v-Src directly bind the C terminus. When expressed in neuroblastoma cells, point mutation of Y2122 prevents both tyrosine phosphorylation of alpha 1C and IGF-1 potentiation. Our data provide a biochemical mechanism whereby phosphorylation of a single specific tyrosine residue rapidly modifies ion channel physiology.

关键词：钙通道激动药/药理学钙通道 L型/药物作用钙通道 L型/遗传学钙通道 L型/生理学催化作用细胞系遗传载体免疫印迹法胰岛素样生长因子ⅰ/药理学诱变定点神经组织蛋白质类/代谢神经元/药物作用膜片钳术磷放射性同位素磷酸酪氨酸/生物合成磷酸酪氨酸/遗传学磷酸酪氨酸/生理学沉淀素试验原癌基因蛋白质pp60(c-src)/代谢刺激化学性酪氨酸/遗传学酪氨酸/生理学 src族激酶类/代谢动物大鼠

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Insulin-like growth factor (IGF)-I regulates IGF-binding protein-5 gene expression through the phosphatidylinositol 3-kinase, protein kinase B/Akt, and p70 S6 kinase signaling pathway

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第52期274卷 37147-37153页

作者： Duan, CM Liimatta, MB Bottum, OL Univ Michigan Dept Biol Ann Arbor MI 48109 USA

Expression of the insulin-like growth factor-binding protein 5 (IGFBP-5) gene in vascular smooth muscle cells is up-regulated by IGF-I through an IGF-I receptor-mediated mechanism. In this study, we studied the possible involvement of the mitogen-activated protein kinase (MAPK) and PI 3-kinase signaling pathways in mediating IGF-I-regulated IGFBP-5 gene expression. The addition of Des(1-3)IGF-1, an IGF analog with reduced affinity to IGFBPs, resulted in a transient activation of p44 and p42 MAPK. Inhibition of the MAPK activation by PD98059, however, did not affect IGF-I-stimulated IGFBP-5 expression. Des(1-3)IGF-I treatment also strongly activated PI 3-kinase. This activation was probably mediated through IRS-1, because IGF-1 stimulation resulted in a significant increase in IRS-1- but not IRS-2-associated PI 3-kinase activity, This activation occurred within 5 min and was sustained at high levels for over 6 h. Likewise, Des(1-3)IGF-I caused a long lasting activation of PKB/Akt and p70(s6k). When LY294002 and wortmannin, two specific inhibitors of PI 3-kinase, were added with Des(1-3)IGF-I, the IGF-I-regulated IGFBP-5 expression was negated. The addition of rapamycin, which inhibits IGF-I-induced p70(s6k) activation, significantly inhibited IGF-I-regulated IGFBP-5 gene expression, These results suggest that the action of IGF-I on IGFBP-5 gene expression requires the activation of the PI 3-kinase-PKB/Akt-p70(s6k) pathway but not the MAPK pathway in vascular smooth muscle cells.

关键词：细胞培养的基因表达调控/药物作用胰岛素样生长因子结合蛋白质5/遗传学胰岛素样生长因子ⅰ/药理学肌平滑血管/细胞学肌平滑血管/代谢磷酸肌醇3-激酶类/生理学蛋白质丝氨酸苏氨酸激酶原癌基因蛋白质类/生理学原癌基因蛋白质c-akt 视网膜母细胞瘤蛋白质/代谢核糖体蛋白质S6激酶类/生理学猪动物

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Effects of insulin and LongR³ on serum-free Chinese hamster ovary cell cultures expressing two recombinant proteins

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BIOTECHNOLOGY PROGRESS 2000年第5期16卷 693-697页

作者： Morris, AE Schmid, J Immunex Res & Dev Corp Seattle WA 98101 USA

Insulin is the most commonly used growth factor for sustaining cell growth and viability in serum-free Chinese hamster ovary (CHO) cell cultures. In the present study insulin and IGF-1 analogue (LongR(3)) were compared for their ability to support growth, viability, and production of two serum-free CHO cell Lines expressing recombinant protein. The first cell line, VA12, expresses protein B, and the second cell line, CL23, expresses protein C. Both molecules are recombinant cytokine receptors. VA12 will grow in serum-free media lacking growth factor, while CL23 requires either insulin or LongR(3) for cell growth. Both cell lines, however, require a growth factor for optimal performance under production conditions. In this study, LongR(3) was better able to sustain the viability of both cell lines under production conditions than insulin. These data indicate that while insulin and LongR(3) can both serve as growth and viability factors for CHO cells, LongR(3) is the preferred growth factor for cell lines VA12 and CL23.

关键词： CHO细胞仓鼠亚科仓鼠属培养基无血清胰岛素/药理学胰岛素样生长因子Ⅰ/类似物和衍生物胰岛素样生长因子ⅰ/药理学卵巢/细胞学卵巢/药物作用卵巢/代谢重组蛋白质类/生物合成动物女(雌)性

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Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第35期274卷 24980-24986页

作者： Kapeller, R Moriarty, A Strauss, A Stubdal, H Theriault, K Siebert, E Chickering, T Morgenstern, JP Tartaglia, LA Lillie, J Millennium Pharmaceut Inc Cambridge MA 02139 USA

A mutation in the tub gene leads to maturity-onset obesity, insulin resistance, and progressive retinal and cochlear degeneration in mice. tub is a member of a growing family of genes that encode proteins of unknown function that are remarkably conserved across species. The absence of obvious transmembrane domain(s) or signal sequence peptide motif(s) suggests that Tub is an intracellular protein. Additional sequence analysis revealed the presence of putative tyrosine phosphorylation motifs and Src homology 2 (SH2)binding sites. Here we demonstrate that in CHO-IR cells, transfected Tub is phosphorylated on tyrosine in response to insulin and insulin-like growth factor-1 and that in PC12 cells, insulin but not EGF induced tyrosine phosphorylation of endogenous Tub. In vitro, Tub is phosphorylated by purified insulin receptor kinase as well as by Abl and JAK 2 but not by epidermal growth factor receptor and Src kinases, Furthermore, upon tyrosine phosphorylation, Tub associated selectively with the SH2 domains of Abl, Lck, and the C-terminal SH2 domain of phospholipase Cy and insulin enhanced the association of Tub with endogenous phospholipase Cy in CHO-IR cells. These data suggest that Tub may function as an adaptor protein linking the insulin receptor, and possibly other protein-tyrosine kinases, to SH2-containing proteins.

关键词：衔接蛋白质类信号转导 CHO细胞仓鼠亚科胰岛素/代谢胰岛素样生长因子ⅰ/药理学 Janus激酶2 癌基因蛋白质v-abl/代谢磷酰化磷酸酪氨酸/代谢蛋白质结合蛋白酪氨酸激酶类/代谢蛋白质类/遗传学蛋白质类/代谢原癌基因蛋白质类受体蛋白质酪氨酸激酶类/代谢受体胰岛素/代谢信号传导转染 src同源域动物

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Growth and antrum formation of bovine preantral follicles in long-term culture in vitro

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BIOLOGY OF REPRODUCTION 2000年第5期62卷 1322-1328页

作者： Gutierrez, CG Ralph, JH Telfer, EE Wilmut, I Webb, R Roslin Inst Roslin EH25 9PS Midlothian Scotland Univ Edinburgh Sch Agr Bldg Div Biol Sci IERM Edinburgh EH9 3JG Midlothian Scotland Univ Nottingham Sch Biol Sci Div Agr & Hort Loughborough LE12 5RD Leics England

Culture of preantral follicles has important biotechnological implications through its potential to produce large quantities of oocytes for embryo production and transfer. A long-term culture system for bovine preantral follicles is described. Bovine preantral follicles (166 +/- 2.15 pm), surrounded by theta cells, were isolated from ovarian cortical slices. Follicles were cultured under conditions known to maintain granulosa cell viability in vitro. The effects of epidermal growth factor (EGF), insulin-like growth factor (IGF)-I, FSH, and coculture with bovine granulosa cells on preantral follicle growth were analyzed. Follicle and oocyte diameter increased significantly (P < 0.05) with time in culture. FSH, IGF-I, and EGF stimulated (P < 0.05) follicle growth rate but had no effect on oocyte growth. Coculture with granulosa cells inhibited FSH/ICF-I-stimulated growth. Most follicles maintained their morphology throughout culture, with the presence of a thecal layer and basement membrane surrounding the granulosa cells. Antrum formation, confirmed by confocal microscopy, occurred between Days 10 and 28 of culture. The probability of follicles reaching antrum development was 0.19 for control follicles. The addition of growth factors or FSH increased (P < 0.05) the probability of antrum development to 0.55. Follicular growth appeared to be halted by slower growth of the basement membrane, as growing follicles occasionally burst the basement membrane, extruding their granulosa cells. In conclusion, a preantral follicle culture system in which follicle morphology can be maintained for up to 28 days has been developed. In this system, FSH, EGF, and IGF-I stimulated follicle growth and enhanced antrum formation. This culture system may provide a valuable approach for studying the regulation of early follicular development and for production of oocytes for nuclear/embryo transfer, but further work is required.

关键词：细胞培养技术/方法细胞分裂/药物作用细胞培养的表皮生长因子/药理学卵泡刺激素/药理学胰岛素样生长因子ⅰ/药理学卵泡/细胞学卵泡/药物作用卵泡/生理学动物牛女(雌)性

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Insulin-like growth factor I synergizes with interleukin 4 for hematopoietic cell proliferation independent of insulin receptor substrate expression

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MOLECULAR AND CELLULAR BIOLOGY 1999年第5期19卷 3816-3828页

作者： Soon, L Flechner, L Gutkind, JS Wang, LH Baserga, R Pierce, JH Li, WQ NCI Cellular & Mol Biol Lab Bethesda MD 20892 USA NIDR Oral & Pharyngeal Canc Branch Bethesda MD 20892 USA CUNY Mt Sinai Sch Med Dept Microbiol New York NY 10029 USA Thomas Jefferson Univ Kimmel Canc Ctr Philadelphia PA 19107 USA

In the present study, we investigated the potential role of insulin-like growth factor I (IGF-I) receptor (IGF-IR) in cell proliferation by overexpressing it in 32D myeloid progenitor cells. The overexpression of IGF-IR caused the transfectants to proliferate in response to IGF-I in the absence of insulin receptor substrate (IRS) expression, The activation of overexpressed wild-type IGF-IR, but not that of an ATP-binding mutant of IGF-IR, resulted in the increased tyrosine phosphorylation of several intracellular proteins, including SHC, Src homology 2-containing inositol-5-phosphatase, protein kinase C-delta, and Erk2, Grb2 association with SHC and mitogen-activated protein kinase (MAPK) activity was also enhanced in response to IGF-I stimulation. Interestingly, the stimulation of the IGF-IR transfectants with interleukin 4 (IL-4) also resulted in strong mitogenesis independent of IRS expression. Moreover, IGF-I and/or IL-4 induced long-term cell growth of the IGF-IR transfectants. IL-4 was able to synergize with IGF-I for DNA synthesis, even in the parental 32D cells and a pro-B-cell line, Baf3, indicating the physiological importance of the two growth factors in hematopoietic cell proliferation. IL-4 stimulation of the IGF-IR transfectants resulted in enhanced tyrosine phosphorylation of SHC, Erk2, and signal transducer and activator of transcription 6 (STAT6) proteins. Both IL-4 and IGF-I were able to induce c-myc early response gene expression, and this expression was maximal in the presence of both factors. Finally, we demonstrated that a MAPK kinase inhibitor was able to suppress mitogenesis of the IGF-IR transfectants in response to IGF-I and/or IL-4. Together, our results suggest that IL-4 synergizes with IGF-I for hematopoietic cell proliferation, likely through cross talk between SHC/Grb2/MAPK and STAT6 pathways and through c-myc gene up-regulation.

关键词：衔接蛋白质类信号转导衔接蛋白质类膜泡运输钙-钙调素依赖性蛋白激酶类/代谢细胞分裂细胞系酶激活 GRB2衔接蛋白质基因表达调控/遗传学基因 myc/遗传学血细胞生成胰岛素受体底物蛋白质类胰岛素样生长因子ⅰ/药理学白细胞介素4/代谢有丝分裂原/代谢突变/遗传学磷酸肌醇3-激酶类/代谢磷蛋白类/遗传学磷蛋白类/代谢磷酰化蛋白质类/代谢受体蛋白质酪氨酸激酶类/代谢受体 IGF1型/遗传学受体 IGF1型/代谢 STAT6转录因子 Shc信号衔接蛋白质类干细胞/代谢反式激活因子类/代谢转染

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