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Table of Contents
Vol. 1, No. 4, 2009
Issue release date: June 2009
J Innate Immun 2009;1:309–321
(DOI:10.1159/000200773)

Tube Is an IRAK-4 Homolog in a Toll Pathway Adapted for Development and Immunity

Towb P. · Sun H. · Wasserman S.A.
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, Calif., USA
email Corresponding Author

Abstract

Acting through the Pelle and IRAK family of protein kinases, Toll receptors mediate innate immune responses in animals ranging from insects to humans. In flies, the Toll pathway also functions in patterning of the syncytial embryo and requires Tube, a Drosophila-specific adaptor protein lacking a catalytic domain. Here we provide evidence that the Tube, Pelle, and IRAK proteins originated from a common ancestral gene. Following gene duplication, IRAK-4, Tube-like kinases, and Tube diverged from IRAK-1, Pelle, and related kinases. Remarkably, the function of Tube and Pelle in Drosophila embryos can be reconstituted in a chimera modeled on the predicted progenitor gene. In addition, a divergent property of downstream transcription factors was correlated with developmental function. Together, these studies reveal previously unrecognized parallels in Toll signaling in fly and human innate immunity and shed light on the evolution of pathway organization and function.


 goto top of outline Key Words

  • Death domain
  • Drosophila
  • Evolution
  • Gene duplication
  • NF-κB
  • Signal transduction

 goto top of outline Abstract

Acting through the Pelle and IRAK family of protein kinases, Toll receptors mediate innate immune responses in animals ranging from insects to humans. In flies, the Toll pathway also functions in patterning of the syncytial embryo and requires Tube, a Drosophila-specific adaptor protein lacking a catalytic domain. Here we provide evidence that the Tube, Pelle, and IRAK proteins originated from a common ancestral gene. Following gene duplication, IRAK-4, Tube-like kinases, and Tube diverged from IRAK-1, Pelle, and related kinases. Remarkably, the function of Tube and Pelle in Drosophila embryos can be reconstituted in a chimera modeled on the predicted progenitor gene. In addition, a divergent property of downstream transcription factors was correlated with developmental function. Together, these studies reveal previously unrecognized parallels in Toll signaling in fly and human innate immunity and shed light on the evolution of pathway organization and function.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Kawai T, Akira S: TLR signaling. Cell Death Differ 2006;13:816–825.
  2. Imler JL, Ferrandon D, Royet J, Reichhart JM, Hetru C, Hoffmann JA: Toll-dependent and Toll-independent immune responses in Drosophila. J Endotoxin Res 2004;10:241–246.
  3. Brennan CA, Anderson KV: Drosophila: the genetics of innate immune recognition and response. Annu Rev Immunol 2004;22:457–483.
  4. Pasare C, Medzhitov R: Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 2005;560:11–18.
  5. Kim T, Kim YJ: Overview of innate immunity in Drosophila. J Biochem Mol Biol 2005;38:121–127.
  6. Halfon MS, Keshishian H: The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo. Dev Biol 1998;199:164–174.
  7. Anderson KV, Bokla L, Nüsslein-Volhard C: Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 1985;42:791–798.
  8. Seppo A, Matani P, Sharrow M, Tiemeyer M: Induction of neuron-specific glycosylation by Tollo/Toll-8, a Drosophila Toll-like receptor expressed in non-neural cells. Development 2003;130:1439–1448.
  9. Qiu P, Pan PC, Govind S: A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis. Development 1998;125:1909–1920.
  10. Belvin MP, Anderson KV: A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol 1996;12:393–416.
  11. Govind S, Nehm RH: Innate immunity in fruit flies: a textbook example of genomic recycling. PLoS Biol 2004;2:e276–e232.
  12. Baeuerle PA, Baltimore D: NF-κB: ten years after. Cell 1996;87:13–20.
  13. Janssens S, Beyaert R: A universal role for MyD88 in TLR/IL-1R-mediated signaling. Trends Biochem Sci 2002;27:474–482.
  14. Chen LY, Wang JC, Hyvert Y, Lin HP, Perrimon N, Imler JL, Hsu JC: Weckle is a zinc finger adaptor of the toll pathway in dorsoventral patterning of the Drosophila embryo. Curr Biol 2006;16:1183–1193.
  15. Tartaglia LA, Ayres TM, Wong GH, Goeddel DV: A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993;74:845–853.
  16. Feinstein E, Kimchi A, Wallach D, Boldin M, Varfolomeev E: The death domain: a module shared by proteins with diverse cellular functions. Trends Biochem Sci 1995;20:342–344.
  17. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV: TRAF6 is a signal transducer for interleukin-1. Nature 1996;383:443–446.
  18. Janssens S, Beyaert R: Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell 2003;11:293–302.
  19. Shelton CA, Wasserman SA: pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo. Cell 1993;72:515–525.
  20. Silverman N, Maniatis T: NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev 2001;15:2321–2342.
  21. Anderson KV, Nüsslein-Volhard C: Information for the dorsal-ventral pattern of the Drosophila embryo is stored as maternal mRNA. Nature 1984;311:223–227.
  22. Letsou A, Alexander S, Orth K, Wasserman SA: Genetic and molecular characterization of tube, a Drosophila gene maternally required for embryonic dorsoventral polarity. Proc Natl Acad Sci USA 1991;88:810–814.
  23. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA: The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–983.
  24. Letsou A, Alexander S, Wasserman SA: Domain mapping of tube, a protein essential for dorsoventral patterning of the Drosophila embryo. EMBO J 1993;12:3449–3458.
  25. Xiao T, Towb P, Wasserman SA, Sprang SR: Three-dimensional structure of a complex between the death domains of Pelle and Tube. Cell 1999;99:545–555.
  26. Sun H, Bristow BN, Qu G, Wasserman SA: A heterotrimeric death domain complex in Toll signaling. Proc Natl Acad Sci USA 2002;99:12871–12876.
  27. Edwards DN, Towb P, Wasserman SA: An activity-dependent network of interactions links the rel protein Dorsal with its cytoplasmic regulators. Development 1997;124:3855–3864.
  28. Yang J, Steward R: A multimeric complex and the nuclear targeting of the Drosophila Rel protein Dorsal. Proc Natl Acad Sci USA 1997;94:14524–14529.
  29. Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR: Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 1989;77:51–59.
  30. Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994;22:4673–4680.
  31. Felsenstein J: PHYLIP – Phylogeny Inference Package (version 3.2). Cladistics 1989;5:164–166.
  32. Anderson KV, Jurgens G, Nüsslein-Volhard C: Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 1985;42:779–789.
  33. Wieschaus E, Nüsslein-Volhard C: Looking at embryos; in Roberts DB (ed): Drosophila: A Practical Approach. Oxford, IRL Press, 1986, pp 199–227.
  34. Roth S, Hiromi Y, Godt D, Nüsslein-Volhard C: Cactus, a maternal gene required for proper formation of the dorsoventral morphogen gradient in Drosophila embryos. Development 1991;112:371–388.
  35. Sun H, Towb P, Chiem DN, Foster BA, Wasserman SA: Regulated assembly of the Toll signaling complex drives Drosophila dorsoventral patterning. EMBO J 2004;23:100–110.
  36. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ: Basic local alignment search tool. J Mol Biol 1990;215:403–410.
  37. Eisenberg D, Marcotte EM, Xenarios I, Yeates TO: Protein function in the post-genomic era. Nature 2000;405:823–826.
  38. Shiu SH, Bleecker AB: Receptor-like kinases from Arabidopsis form a monophyletic gene family related to animal receptor kinases. Proc Natl Acad Sci USA 2001;98:10763–10768.
  39. Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM: Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 1991;253:407–414.
  40. Russo AA, Jeffrey PD, Pavletich NP: Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol 1996;3:696–700.
  41. Yamaguchi H, Hendrickson WA: Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature 1996;384:484–489.
  42. Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ: Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 1997;90:859–869.
  43. Cao Z, Henzel WJ, Gao X: IRAK: a kinase associated with the interleukin-1 receptor. Science 1996;271:1128–1131.
  44. Li S, Strelow A, Fontana EJ, Wesche H: IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA 2002;99:5567–5572.
  45. Lasker MV, Gajjar MM, Nair SK: Cutting edge: molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling. J Immunol 2005;175:4175–4179.
  46. Charatsi I, Luschnig S, Bartoszewski S, Nüsslein-Volhard C, Moussian B: Krapfen/dMyd88 is required for the establishment of dorsoventral pattern in the Drosophila embryo. Mech Dev 2003;120:219–226.
  47. Towb P, Bergmann A, Wasserman SA: The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development 2001;128:4729–4736.
  48. Galindo RL, Edwards DN, Gillespie SK, Wasserman SA: Interaction of the pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. Development 1995;121:2209–2218.
  49. Dodelet VC, Pasquale EB: Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene 2000;19:5614.
  50. Seidel-Dugan C, Meyer BE, Thomas SM, Brugge JS: Effects of SH2 and SH3 deletions on the functional activities of wild-type and transforming variants of c-Src. Mol Cell Biol 1992;12:1835–1845.
  51. Grosshans J, Bergmann A, Haffter P, Nüsslein-Volhard C: Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo. Nature 1994;372:563–566.
  52. Towb P, Galindo RL, Wasserman SA: Recruitment of Tube and Pelle to signaling sites at the surface of the Drosophila embryo. Development 1998;125:2443–2450.
  53. Grosshans J, Schnorrer F, Nüsslein-Volhard C: Oligomerisation of Tube and Pelle leads to nuclear localisation of dorsal. Mech Dev 1999;81:127–138.
  54. Chasan R, Anderson KV: Maternal control of dorsal-ventral polarity and pattern in the embryo; in Bate M, Martinez Arias A (eds): The Development of Drosophila melanogaster. New York, Cold Spring Harbor Laboratory Press, 1993, vol 1, pp 387–432.
  55. Hecht PM, Anderson KV: Genetic characterization of tube and pelle, genes required for signaling between Toll and dorsal in the specification of the dorsal-ventral pattern of the Drosophila embryo. Genetics 1993;135:405–417.
  56. Manfruelli P, Reichhart JM, Steward R, Hoffmann JA, Lemaitre B: A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF. EMBO J 1999;18:3380–3391.
  57. Meng X, Khanuja BS, Ip YT: Toll receptor-mediated Drosophila immune response requires Dif, an NF-κB factor. Genes Dev 1999;13:792–797.
  58. Ip YT, Reach M, Engstrom Y, Kadalayil L, Cai H, Gonzalez-Crespo S, Tatei K, Levine M: Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell 1993;75:753–763.
  59. Rutschmann S, Jung AC, Hetru C, Reichhart JM, Hoffmann JA, Ferrandon D: The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila. Immunity 2000;12:569–580.
  60. Dushay MS, Asling B, Hultmark D: Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila. Proc Natl Acad Sci USA 1996;93:10343–10347.
  61. Silverman N, Zhou R, Stoven S, Pandey N, Hultmark D, Maniatis T: A Drosophila IκB kinase complex required for Relish cleavage and antibacterial immunity. Genes Dev 2000;14:2461–2471.
  62. Stoven S, Ando I, Kadalayil L, Engstrom Y, Hultmark D: Activation of the Drosophila NF-κB factor Relish by rapid endoproteolytic cleavage. EMBO Rep 2000;1:347–352.
  63. Suzuki N, Suzuki S, Millar DG, Unno M, Hara H, Calzascia T, Yamasaki S, Yokosuka T, Chen NJ, Elford AR, Suzuki J, Takeuchi A, Mirtsos C, Bouchard D, Ohashi PS, Yeh WC, Saito T: A critical role for the innate immune signaling molecule IRAK-4 in T cell activation. Science 2006;311:1927–1932.
  64. Dardick C, Ronald P: Plant and animal pathogen recognition receptors signal through non-RD kinases. PLoS Pathog 2006;2:e2.
  65. Shen B, Manley JL: Phosphorylation modulates direct interactions between the Toll receptor, Pelle kinase and Tube. Development 1998;125:4719–4728.
  66. Shen B, Manley JL: Pelle kinase is activated by autophosphorylation during Toll signaling in Drosophila. Development 2002;129:1925–1933.
  67. Stein D, Goltz JS, Jurcsak J, Stevens L: The Dorsal-related immunity factor (Dif) can define the dorsal-ventral axis of polarity in the Drosophila embryo. Development 1998;125:2159–2169.
  68. Chen G, Handel K, Roth S: The maternal NF-κB/dorsal gradient of Tribolium castaneum: dynamics of early dorsoventral patterning in a short-germ beetle. Development 2000;127:5145–5156.
  69. Moussian B, Roth S: Dorsoventral axis formation in the Drosophila embryo – shaping and transducing a morphogen gradient. Curr Biol 2005;15:R887–R899.

 goto top of outline Author Contacts

Dr. Steven A. Wasserman
Section of Cell and Developmental Biology, Division of Biological Sciences
University of California at San Diego, Bonner Hall, Room 4402, MC 0349
9500 Gilman Drive, La Jolla, CA 92093-0349 (USA)
Tel. +1 858 822 2408, Fax +1 858 822 3201, E-Mail stevenw@ucsd.edu


 goto top of outline Article Information

Received: October 1, 2008
Accepted after revision: November 4, 2008
Published online: February 10, 2009
Number of Print Pages : 13
Number of Figures : 6, Number of Tables : 2, Number of References : 69


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 1, No. 4, Year 2009 (Cover Date: April 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Acting through the Pelle and IRAK family of protein kinases, Toll receptors mediate innate immune responses in animals ranging from insects to humans. In flies, the Toll pathway also functions in patterning of the syncytial embryo and requires Tube, a Drosophila-specific adaptor protein lacking a catalytic domain. Here we provide evidence that the Tube, Pelle, and IRAK proteins originated from a common ancestral gene. Following gene duplication, IRAK-4, Tube-like kinases, and Tube diverged from IRAK-1, Pelle, and related kinases. Remarkably, the function of Tube and Pelle in Drosophila embryos can be reconstituted in a chimera modeled on the predicted progenitor gene. In addition, a divergent property of downstream transcription factors was correlated with developmental function. Together, these studies reveal previously unrecognized parallels in Toll signaling in fly and human innate immunity and shed light on the evolution of pathway organization and function.



 goto top of outline Author Contacts

Dr. Steven A. Wasserman
Section of Cell and Developmental Biology, Division of Biological Sciences
University of California at San Diego, Bonner Hall, Room 4402, MC 0349
9500 Gilman Drive, La Jolla, CA 92093-0349 (USA)
Tel. +1 858 822 2408, Fax +1 858 822 3201, E-Mail stevenw@ucsd.edu


 goto top of outline Article Information

Received: October 1, 2008
Accepted after revision: November 4, 2008
Published online: February 10, 2009
Number of Print Pages : 13
Number of Figures : 6, Number of Tables : 2, Number of References : 69


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 1, No. 4, Year 2009 (Cover Date: April 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Kawai T, Akira S: TLR signaling. Cell Death Differ 2006;13:816–825.
  2. Imler JL, Ferrandon D, Royet J, Reichhart JM, Hetru C, Hoffmann JA: Toll-dependent and Toll-independent immune responses in Drosophila. J Endotoxin Res 2004;10:241–246.
  3. Brennan CA, Anderson KV: Drosophila: the genetics of innate immune recognition and response. Annu Rev Immunol 2004;22:457–483.
  4. Pasare C, Medzhitov R: Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 2005;560:11–18.
  5. Kim T, Kim YJ: Overview of innate immunity in Drosophila. J Biochem Mol Biol 2005;38:121–127.
  6. Halfon MS, Keshishian H: The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo. Dev Biol 1998;199:164–174.
  7. Anderson KV, Bokla L, Nüsslein-Volhard C: Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 1985;42:791–798.
  8. Seppo A, Matani P, Sharrow M, Tiemeyer M: Induction of neuron-specific glycosylation by Tollo/Toll-8, a Drosophila Toll-like receptor expressed in non-neural cells. Development 2003;130:1439–1448.
  9. Qiu P, Pan PC, Govind S: A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis. Development 1998;125:1909–1920.
  10. Belvin MP, Anderson KV: A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol 1996;12:393–416.
  11. Govind S, Nehm RH: Innate immunity in fruit flies: a textbook example of genomic recycling. PLoS Biol 2004;2:e276–e232.
  12. Baeuerle PA, Baltimore D: NF-κB: ten years after. Cell 1996;87:13–20.
  13. Janssens S, Beyaert R: A universal role for MyD88 in TLR/IL-1R-mediated signaling. Trends Biochem Sci 2002;27:474–482.
  14. Chen LY, Wang JC, Hyvert Y, Lin HP, Perrimon N, Imler JL, Hsu JC: Weckle is a zinc finger adaptor of the toll pathway in dorsoventral patterning of the Drosophila embryo. Curr Biol 2006;16:1183–1193.
  15. Tartaglia LA, Ayres TM, Wong GH, Goeddel DV: A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993;74:845–853.
  16. Feinstein E, Kimchi A, Wallach D, Boldin M, Varfolomeev E: The death domain: a module shared by proteins with diverse cellular functions. Trends Biochem Sci 1995;20:342–344.
  17. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV: TRAF6 is a signal transducer for interleukin-1. Nature 1996;383:443–446.
  18. Janssens S, Beyaert R: Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell 2003;11:293–302.
  19. Shelton CA, Wasserman SA: pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo. Cell 1993;72:515–525.
  20. Silverman N, Maniatis T: NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev 2001;15:2321–2342.
  21. Anderson KV, Nüsslein-Volhard C: Information for the dorsal-ventral pattern of the Drosophila embryo is stored as maternal mRNA. Nature 1984;311:223–227.
  22. Letsou A, Alexander S, Orth K, Wasserman SA: Genetic and molecular characterization of tube, a Drosophila gene maternally required for embryonic dorsoventral polarity. Proc Natl Acad Sci USA 1991;88:810–814.
  23. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA: The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–983.
  24. Letsou A, Alexander S, Wasserman SA: Domain mapping of tube, a protein essential for dorsoventral patterning of the Drosophila embryo. EMBO J 1993;12:3449–3458.
  25. Xiao T, Towb P, Wasserman SA, Sprang SR: Three-dimensional structure of a complex between the death domains of Pelle and Tube. Cell 1999;99:545–555.
  26. Sun H, Bristow BN, Qu G, Wasserman SA: A heterotrimeric death domain complex in Toll signaling. Proc Natl Acad Sci USA 2002;99:12871–12876.
  27. Edwards DN, Towb P, Wasserman SA: An activity-dependent network of interactions links the rel protein Dorsal with its cytoplasmic regulators. Development 1997;124:3855–3864.
  28. Yang J, Steward R: A multimeric complex and the nuclear targeting of the Drosophila Rel protein Dorsal. Proc Natl Acad Sci USA 1997;94:14524–14529.
  29. Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR: Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 1989;77:51–59.
  30. Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994;22:4673–4680.
  31. Felsenstein J: PHYLIP – Phylogeny Inference Package (version 3.2). Cladistics 1989;5:164–166.
  32. Anderson KV, Jurgens G, Nüsslein-Volhard C: Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 1985;42:779–789.
  33. Wieschaus E, Nüsslein-Volhard C: Looking at embryos; in Roberts DB (ed): Drosophila: A Practical Approach. Oxford, IRL Press, 1986, pp 199–227.
  34. Roth S, Hiromi Y, Godt D, Nüsslein-Volhard C: Cactus, a maternal gene required for proper formation of the dorsoventral morphogen gradient in Drosophila embryos. Development 1991;112:371–388.
  35. Sun H, Towb P, Chiem DN, Foster BA, Wasserman SA: Regulated assembly of the Toll signaling complex drives Drosophila dorsoventral patterning. EMBO J 2004;23:100–110.
  36. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ: Basic local alignment search tool. J Mol Biol 1990;215:403–410.
  37. Eisenberg D, Marcotte EM, Xenarios I, Yeates TO: Protein function in the post-genomic era. Nature 2000;405:823–826.
  38. Shiu SH, Bleecker AB: Receptor-like kinases from Arabidopsis form a monophyletic gene family related to animal receptor kinases. Proc Natl Acad Sci USA 2001;98:10763–10768.
  39. Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM: Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 1991;253:407–414.
  40. Russo AA, Jeffrey PD, Pavletich NP: Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol 1996;3:696–700.
  41. Yamaguchi H, Hendrickson WA: Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature 1996;384:484–489.
  42. Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ: Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 1997;90:859–869.
  43. Cao Z, Henzel WJ, Gao X: IRAK: a kinase associated with the interleukin-1 receptor. Science 1996;271:1128–1131.
  44. Li S, Strelow A, Fontana EJ, Wesche H: IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA 2002;99:5567–5572.
  45. Lasker MV, Gajjar MM, Nair SK: Cutting edge: molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling. J Immunol 2005;175:4175–4179.
  46. Charatsi I, Luschnig S, Bartoszewski S, Nüsslein-Volhard C, Moussian B: Krapfen/dMyd88 is required for the establishment of dorsoventral pattern in the Drosophila embryo. Mech Dev 2003;120:219–226.
  47. Towb P, Bergmann A, Wasserman SA: The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development 2001;128:4729–4736.
  48. Galindo RL, Edwards DN, Gillespie SK, Wasserman SA: Interaction of the pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. Development 1995;121:2209–2218.
  49. Dodelet VC, Pasquale EB: Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene 2000;19:5614.
  50. Seidel-Dugan C, Meyer BE, Thomas SM, Brugge JS: Effects of SH2 and SH3 deletions on the functional activities of wild-type and transforming variants of c-Src. Mol Cell Biol 1992;12:1835–1845.
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