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Structural basis for specificity switching of the Src SH2 domain

MOLECULAR CELL 2000年第6期5卷 1043-1049页

作者： Kimber, MS Nachman, J Cunningham, AM Gish, GD Pawson, T Pai, EF Univ Toronto Dept Mol & Med Genet Toronto ON M5S 1A8 Canada Univ Toronto Dept Biochem Toronto ON M5S 1A8 Canada Univ Toronto Dept Med Biophys Toronto ON M5S 1A8 Canada Univ Toronto Prot Engn Network Ctr Excellence Toronto ON M5S 1A8 Canada Mt Sinai Hosp Samuel Lunenfeld Res Inst Programme Mol Biol & Canc Toronto ON M5G 1X5 Canada

The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended conformation with a hydrophobic pocket, which includes ThrEF1, binding IIe(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an Asn(pY +2) requirement, yielding a biological mimic of the GrbP SH2 domain. Here we show that the Src ThrEF1TrpSH2 domain mutant binds pYVNV phosphopeptides in a beta turn conformation, which, despite differing conformations of the interacting tryptophan, closely resembles the native Grb2/pYVNV cognate peptide binding mode. The ThrEF1Trp substitution therefore switches specificity by physically occluding the pTyr +3 binding pocket and by providing additional interaction surface area for Asn(pY +2). This demonstrates structurally how novel SH2 domain specificities may rapidly evolve through single amino acid substitutions and suggests how new signaling pathways may develop.

关键词：衔接蛋白质类信号转导氨基酸序列氨基酸取代结合部位鸡结晶学 X线进化分子 GRB2衔接蛋白质配体模型分子突变磷肽类/化学磷肽类/代谢蛋白质结合蛋白质构象蛋白酪氨酸激酶类/化学蛋白酪氨酸激酶类/遗传学蛋白酪氨酸激酶类/代谢蛋白质类/化学蛋白质类/代谢信号传导/遗传学底物特异性 src同源域/遗传学 src族激酶类动物

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Nuclear retention of IκBα protects it from signal-induced degradation and inhibits nuclear factor κB transcriptional activation

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第13期274卷 9108-9115页

作者： Rodriguez, MS Thompson, J Hay, RT Dargemont, C Univ St Andrews Sch Biomed Sci Inst Biomol Sci St Andrews KY16 9TS Fife Scotland Inst Curie CNRS Unite Mixte Rech 144 F-75248 Paris 05 France

Transcriptional activation of nuclear factor kappa B (NF-kappa B) is mediated by signal-induced phosphorylation and degradation of its inhibitor, I kappa B alpha. However, NF-kappa B activation induces rapid resynthesis of I kappa B alpha, which is responsible for post-induction repression of transcription. Newly synthesized I kappa B alpha translocates to the nucleus, where it dissociates NF-kappa B from DNA and transports NF-kappa B from the nucleus to the cytoplasm in a nuclear export sequence-dependent process that is sensitive to leptomycin B (LMB), In the present study, LMB was used as a tool to inhibit nuclear export sequence-mediated nuclear protein export and evaluate the consequences for regulation of NF-kappa B-dependent transcriptional activity. Pretreatment of cells with LMB inhibits NF-kappa B-dependent transcriptional activation mediated by interleukin 1 beta or tumor necrosis factor alpha. This is a consequence of the inhibition of signal-induced degradation of I kappa B alpha. Although LMB treatment does not affect the signal transduction pathway leading to I kappa B alpha degradation, it blocks I kappa B alpha nuclear export. I kappa B alpha is thus accumulated in the nucleus, and in this compartment it is resistant to signal-induced degradation. These results indicate that the signal-induced degradation of I kappa B alpha is mainly, if not exclusively, a cytoplasmic process. An efficient nuclear export of I kappa B alpha is therefore essential for maintaining a low level of I kappa B alpha in the nucleus and allowing NF-kappa B to be transcriptionally active upon cell stimulation.

关键词：生物转运/遗传学 DNA结合蛋白质类/代谢脂肪酸类不饱和/药理学荧光抗体技术基因报告/遗传学 HeLa细胞 I-κB蛋白质类白细胞介素1/药理学 NF-κB/遗传学 NF-κB/代谢核蛋白质类/遗传学阻遏蛋白质类/遗传学信号传导/遗传学转录遗传/遗传学转录激活/遗传学肿瘤坏死因子α/药理学人类

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Platelet-derived growth factor induces interleukin-6 transcription in osteoblasts through the activator protein-1 complex and activating transcription factor-2

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第10期274卷 6783-6789页

作者： Franchimont, N Durant, D Rydziel, S Canalis, E St Francis Hosp & Med Ctr Res Dept Worcester MA 01605 USA St Francis Hosp & Med Ctr Dept Med Worcester MA 01605 USA Univ Connecticut Sch Med Farmington CT 06030 USA

Platelet-derived growth factor (PDGF) BE, a mitogen that stimulates bone resorption, increases the expression of interleukin-6 (IL-6), a cytokine that induces osteoclast recruitment. The mechanisms involved in IL-6 induction by PDGF BE are poorly understood. We examined the effect of PDGF BE on IL-6 expression in cultures of osteoblasts from fetal rat calvariae (Ob cells). PDGF BE increased IL-6 mRNA and heterogeneous nuclear RNA levels, the rate of transcription, and the activity of base pairs (bp) -2906 to +20 IL-6 promoter fragments transiently transfected into Ob cells. Deletion analysis revealed two responsive regions, one containing an activator protein-1 (AP-1) site located between bp -276 and -257, and a second, less well defined, downstream of -257. Targeted mutations of a cyclic AMP-responsive element (CRE), and nuclear factor-IL-6 and nuclear factor-kappa B binding sites in a bp -257 to +20 IL-6 construct that was transfected into Ob cells, revealed that the CRE also contributed to IL-6 promoter induction by PDGF BE. Electrophoretic mobility shift assay revealed AP-1 and CRE nuclear protein complexes that were enhanced by PDGF BE. Supershift assays revealed binding of Jun and Fos to AP-1 and CRE sequences and binding of activating transcription factor-a to CRE. In conclusion, PDGF BE induces IL-6 transcription in osteoblasts by regulating nuclear proteins of the AP-1 complex and activating transcription factor-2.

关键词：转录激活因子2 cAMP反应元件结合蛋白质/遗传学 cAMP反应元件结合蛋白质/代谢白细胞介素6/生物合成白细胞介素6/遗传学成骨细胞/代谢血小板源性生长因子/药理学 RNA 信使/分析 RNA 信使/生物合成信号传导/药物作用信号传导/遗传学转录因子AP-1/遗传学转录因子AP-1/代谢转录因子/遗传学转录因子/代谢转录遗传/药物作用动物大鼠

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Evidence for a p21^ras/Raf-1/MEK-1/ERK-2-independent pathway in stimulation of IL-2 gene transcription in human primary T lymphocytes

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第36期274卷 25743-25748页

作者： Lafont, V Ottones, F Liautard, J Favero, J Univ Montpellier 2 INSERM U431 F-34095 Montpellier 05 France Imperial Canc Res Fund Lymphocyte Activat Lab London WC2A 3PX England

T cell stimulation leads to triggering of signals transmitted from the cell membrane to the nucleus through TCR/CD3 proteins. Characterization of these signals largely results from the use of cell lines stimulated with anti-CDB monoclonal antibodies. These studies have established that activation caused a rapid increase in the formation of GTP-bound has, which stimulates the mitogen-activated protein kinase pathway involving the extracellular-regulated kinase-2 (ERK-2) and activates the nuclear factor of activated T cells (NF-AT) that regulates interleukin-2 (IL-2) gene transcription. In the present study, we used human primary T cells, and we investigated the intracellular signals triggered by two different anti-CD3 monoclonal antibodies (UCHT1 and X-35), which both strongly induce cell proliferation. We found that, in contrast to the commonly used UCHT1, X-35 activated IL-2 gene transcription without stimulation of the Raf-1/mitogen-activated ERK kinase-1 (MEK-1)/ERK-2 phosphorylation cascade;we also showed that X-35 stimulation, which triggers an ERK-2-independent pathway, does not involve activation of p21(ras). In addition to demonstrating that activation of p21(ras) and of its Raf-1/MEK-1/ERK-2 effector pathway is not an event obligatorily triggered upon TCR/CD3 ligation, these results provide the first evidence of the existence of a p21(ras)/ERK-2-independent pathway for IL-2 gene transcription in human primary T lymphocytes.

关键词：细胞培养的白细胞介素1/生物合成白细胞介素1/遗传学淋巴细胞活化丝裂原活化蛋白激酶1/遗传学丝裂原活化蛋白激酶1/代谢原癌基因蛋白质c-raf/遗传学原癌基因蛋白质c-raf/代谢原癌基因蛋白质p21(ras)/遗传学原癌基因蛋白质p21(ras)/代谢信号传导/遗传学信号传导/免疫学 T淋巴细胞/免疫学 T淋巴细胞/代谢转录遗传人类

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Hos5 -: a negative regulator of osmotic stress-induced gene expression in Arabidopsis thaliana

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PLANT JOURNAL 1999年第5期19卷 569-578页

作者： Xiong, LM Ishitani, M Lee, HJ Zhu, JK Univ Arizona Dept Plant Sci Tucson AZ 85721 USA

Osmotic stress activates the expression of many plant genes through ABA-dependent as well as ABA-independent signaling pathways. We report here the characterization of a novel mutant of Arabidopsis thaliana, hos5-1, which exhibits increased expression of the osmotic stress responsive RD29A gene. The expression of several other stress genes are also enhanced by the hos5-1 mutation. The enhanced expression is specific to ABA and osmotic stress because low temperature regulation of these genes is not altered in the mutant. Genetic analysis indicated that hos5-1 is a recessive mutation in a single nuclear gene on chromosome ill. Double mutant analysis of hos5-1 and the ABA-deficient aba1-1 as well as the ABA-insensitive abi1-1 mutant indicated that the osmotic stress hypersensitivity of hos5-1 is not affected by ABA deficiency or insensitivity. Furthermore, combined treatments of hos5-1 with ABA and osmotic stress had an additive effect on RD29A-LUC expression. These results suggest that the osmotic stress hypersensitivity in hos5-1 may be ABA-independent. The germination of hos5-1 seeds was more resistant to ABA. However, the hos5-1 mutation did not influence stomatal control and only slightly affected the regulation of growth and proline accumulation by ABA. The hos5-1 mutation reveals a negative regulator of osmotic stress-responsive gene expression shared by ABA-dependent and ABA-independent osmotic stress signaling pathways.

关键词：拟南芥属/遗传学基因表达调控植物渗透压植物基因修饰信号传导/遗传学

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Activation of the AT₁ angiotensin receptor is dependent on adjacent apolar residues in the carboxyl terminus of the third cytoplasmic loop

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第21期275卷 15782-15788页

作者： Zhang, M Zhao, X Chen, HC Catt, KJ Hunyady, L Semmelweis Univ Sch Med Dept Physiol H-1444 Budapest Hungary NICHD Endocrinol & Reprod Res Branch NIH Bethesda MD 20892 USA

The C-terminal region of the third intracellular loop of the AT(1) angiotensin receptor (AT(1)-R) is an important determinant of G protein coupling. The roles of individual residues in agonist-induced activation of G(q/11)-dependent phosphoinositide hydrolysis were determined by mutational analysis of the amino acids in this region. Functional studies on mutant receptors transiently expressed in COS-7 cells showed that alanine substitutions of the amino acids in positions 232-240 of the third loop had no major effect on signal generation. However, deletion mutations that removed Ile(238) or affected its position relative to transmembrane helix VI significantly impaired angiotensin II-induced inositol phosphate responses. Substitution of Ile(238) with an acidic residue abolished the ability of the receptor to mediate inositol phosphate production, whereas its replacement with basic or polar residues reduced the amplitude of inositol phosphate responses. Substitutions of Phe(239) with polar residues had relatively minor effects on inositol phosphate signal generation, but its replacement by aspartic acid reduced, and by positively charged residues (Lys, Arg) significantly increased, angiotensin II-induced inositol phosphate responses. The internalization kinetics of the Ile(238) and Phe239 mutant receptors were impaired in parallel with the reduction in their signaling responses. These findings have identified Ile238 and Phe239 as the critical residues in the C-terminal region of the third intracellular loop of the AT(1)-R for receptor activation. They also suggest that an apolar amino acid corresponding to Ile(238) of the AT(1)-R is a general requirement for activation of other G protein-coupled receptors by their agonist ligands.

关键词：血管紧张素Ⅱ/药理学 COS细胞 GTP结合蛋白质类/代谢肌醇磷酸类/代谢动力学膜蛋白质类/化学膜蛋白质类/遗传学突变蛋白质结合受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/激动剂受体血管紧张素/化学受体血管紧张素/遗传学信号传导/遗传学转染动物大鼠

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Convergent pathways for lipochitooligosaccharide and auxin signaling in tobacco cells

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1996年第23期93卷 13389-13392页

作者： Rohrig, H Schmidt, J Walden, R Czaja, I Lubenow, H Wieneke, U Schell, J John, M Max-Planck-Institut für Züchtungsforschung Carl-von-Linné-Weg 10 D-50829 Köln Germany.

Lipochitooligosaccharides (LCOs) are a novel class of plant growth regulators that activate in tobacco protoplasts the expression of AXI1, a gene implicated in auxin signaling. Transient assays with a chimeric P-AXI-GUS expression plasmid revealed that the N-octadecenoylated monosaccharide GlcN has all structural requirements for a biological active glycolipid, whereas the inactive N-acylated GalN epimer inhibits LCO action. Specific inhibition of LCO and auxin action shows that both signals are transduced within the tobacco cell via separate pathways that converge at or before AXI1 transcription. Cytokinin is suggested to be a common effector of LCO and auxin signaling. We also show that activation of AXI1 correlates with growth factor-induced cell division.

关键词：拟南芥蛋白质类/遗传学印迹法 RNA 细胞分裂/药物作用细胞分裂/遗传学细胞培养的细胞激肽类/药理学剂量效应关系药物药物协同作用基因表达调控植物/药物作用葡糖醛酸糖苷酶/遗传学吲哚乙酸类/药理学脂多糖类/化学脂多糖类/药理学模型遗传学植物生长调节物/化学植物生长调节物/药理学启动区遗传/遗传学原生质体/细胞学原生质体/药物作用原生质体/代谢重组融合蛋白质类/遗传学重组融合蛋白质类/代谢信号传导/遗传学烟草/细胞学转录遗传/药物作用转染

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Components of the SWI/SNF complex are required for asymmetric cell division in C-elegans

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MOLECULAR CELL 2000年第3期6卷 617-624页

作者： Sawa, H Kouike, H Okano, H Japan Sci & Technol Corp PRESTO Suita Osaka 5650871 Japan Osaka Univ Grad Sch Med Div Neuroanat Suita Osaka 5650871 Japan Japan Sci & Technol Corp CREST Osaka Japan

Asymmetric cell division is a fundamental process that produces cellular diversity during development. We have identified two mutants in C. elegans (psa-1 and psa-4) in which the asymmetry of T cell division is disrupted. psa-1 and psa-4 encode homologs of yeast SWI3 and SWI2/SNF2, respectively, which are components of the SWI/SNF complex. We show by RNA interference assay that homologs of other components of SWI/SNF are also involved in T cell division. psa-1 and psa-4 are likely to be required in the T cell during mitosis to cause asymmetric cell division. Because the SWI/SNF complex is required for asymmetric division in S. cerevisiae, these results demonstrate that at least some aspects of the mechanism of asymmetric cell division are conserved between yeast and a multicellular organism.

关键词：腺苷三磷酸酶类秀丽新小杆线虫/细胞学秀丽新小杆线虫/遗传学染色体图克隆分子 DNA结合蛋白质类/遗传学真菌蛋白质类/遗传学有丝分裂/遗传学分子序列数据突变/生理学核蛋白质类/遗传学原癌基因蛋白质类/生理学酿酒酵母蛋白质类信号传导/遗传学 T淋巴细胞/细胞学 T淋巴细胞/生理学反式激活因子类转录因子/遗传学 Wnt蛋白质类斑马鱼蛋白质类动物

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Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin

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NATURE IMMUNOLOGY 2000年第1期1卷 59-64页

作者： Pandey, A Ozaki, K Baumann, H Levin, SD Puel, A Farr, AG Ziegler, SF Leonard, WJ Lodish, HF NHLBI Lab Mol Immunol NIH Bethesda MD 20892 USA Brigham & Womens Hosp Dept Pathol Boston MA 02115 USA Whitehead Inst Biomed Res Cambridge MA 02142 USA Roswell Pk Canc Inst Dept Mol & Cellular Biol Buffalo NY 14263 USA Univ Washington Dept Immunol Seattle WA 98195 USA Univ Washington Dept Biol Struct Seattle WA 98195 USA Virginia Mason Res Ctr Seattle WA 98101 USA MIT Dept Biol Cambridge MA 02142 USA

Signaling by type 1 cytokines involves the formation of receptor homodimers, heterodimers or higher order receptor oligomers. Here we report the cloning of a type I cytokine receptor subunit that is most closely related to the common cytokine receptor gamma chain (gamma(c)). Binding and crosslinking experiments demonstrate that this protein is the receptor for a recently described interleukin 7 (IL-7)-like factor, thymic stromal lymphopoietin (TSLP). Binding of TSLP to the thymic stromal lymphopoietin receptor (TSLPR) is increased markedly in the presence of the IL-7 receptor alpha chain (IL-7R alpha). IL-7R alpha-expressing but not parental 32D cells proliferate in the presence of exogenous TSLP, Moreover, a combination of IL-7R alpha and TSLPR is required for TSLP-dependent activation of a STAT5-dependent reporter construct. Thus it is shown that IL-7R alpha is a component of both the IL-7 and TSLP receptors, which helps to explain why deletion of the gene that encodes IL-7R alpha affects the lymphoid system more severely than deletion of the gene encoding IL-7 does. Cloning of TSLPR should facilitate an understanding of TSLP function and its signaling mechanism.

关键词：氨基酸序列克隆分子白细胞介素7/免疫学分子序列数据受体白细胞介素7/遗传学受体白细胞介素7/免疫学信号传导/遗传学信号传导/免疫学胸腺/免疫学

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SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第46期274卷 32662-32666页

作者： Beitz, LO Fruman, DA Kurosaki, T Cantley, LC Scharenberg, AM Harvard Univ Sch Med Lab Allergy & Immunol Boston MA 02215 USA Harvard Univ Sch Med Beth Israel Deaconess Med Ctr Div Signal Transduct Boston MA 02215 USA Harvard Univ Sch Med Dept Pathol Boston MA 02215 USA Harvard Univ Sch Med Dept Cell Biol Boston MA 02215 USA Kansai Med Univ Dept Mol Genet Moriguchi Osaka 570 Japan

We have recently demonstrated that the D3-phosphoinositide phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P-3) is critical for producing sustained calcium signals through its role in promoting the function of TEC family tyrosine kinases such as Bruton's tyrosine kinase. Although PtdIns-3,4,5-P-3 can potentially be synthesized by any of several types of phosphoinositide 3-kinases (PI3Ks), B cell receptor (BCR)-induced PtdIns-3,4,5-P-3 production is thought to occur primarily through the activation of the class Ia (p85/p110) PI3Ks. This process has been proposed to be mediated by an interaction between the Src family kinase LYN and the p85 subunit of FISH and/or through p85 membrane recruitment mediated by CBL and/or CD19. However, calcium signaling and other PI3K-dependent signals are relatively preserved in a LYN kinase-deficient B lymphocyte cell line, suggesting that an alternative pathway for PI3K, activation exists. As SYK/ZAP70 kinases are upstream from many BCR-initiated signaling events, we directly analyzed SYM-dependent accumulation of both PtdIns-3,4,5-P-3 and PtdIns-3,4-P-2 in B cell receptor signaling using both dominant negative and genetic knockout approaches. Both methods indicate that SYK is upstream of, and necessary for, a significant portion of BCR-induced PtdIns-3,4,5-P-3 production. Whereas CD19 does not appear 60 be involved in this SYM-dependent pathway, the SYK substrate CEL is likely involved as the dominant negative SYK markedly attenuates CBL tyrosine phosphorylation and completely blocks the BCR-dependent association of CBL with p85 PI3K.

关键词：抗原 CD19/代谢钙/代谢酶激活酶前体/遗传学细胞内信号肽和蛋白质类淋巴细胞原癌基因蛋白质v-cbl 磷酸肌醇3-激酶类/遗传学磷脂酰肌醇磷酸盐类/代谢磷酰化磷酸酪氨酸/代谢蛋白酪氨酸激酶类/遗传学逆转录病毒科蛋白质类致癌/代谢信号传导/遗传学动物小鼠

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