Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Nov 8;91(23):11256–11260. doi: 10.1073/pnas.91.23.11256

Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase.

S Tsukada 1, M I Simon 1, O N Witte 1, A Katz 1
PMCID: PMC45206  PMID: 7972043

Abstract

Bruton tyrosine kinase (Btk) has been implicated as the defective gene in both human and murine B-cell deficiencies. The identification of molecules that interact with Btk may shed light on critical processes in lymphocyte development. The N-terminal unique region of Btk contains a pleckstrin homology domain. This domain is found in a broad array of signaling molecules and implicated to function in protein-protein interactions. By using an in vitro binding assay and an in vivo competition assay, the pleckstrin homology domain of Btk was shown to interact with the beta gamma dimer of heterotrimeric guanine nucleotide-binding proteins (G proteins). A highly conserved tryptophan residue in subdomain 6 of the pleckstrin homology domain was shown to play a critical role in the binding. The interaction of Btk with beta gamma suggests the existence of a unique connection between cytoplasmic tyrosine kinases and G proteins in cellular signal transduction.

Full text

PDF
11256

Images in this article

11257Image
on p.11257
11258Image
on p.11258
11259Image
on p.11259

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berridge M. J., Dawson R. M., Downes C. P., Heslop J. P., Irvine R. F. Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem J. 1983 May 15;212(2):473–482. doi: 10.1042/bj2120473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blank J. A., Clark G. C., Wiegand G., Luster M. I. Pertussis toxin inhibition of anti-immunoglobulin-stimulated proliferation and inositol phosphate formation. Toxicol Appl Pharmacol. 1990 Nov;106(2):278–286. doi: 10.1016/0041-008x(90)90247-r. [DOI] [PubMed] [Google Scholar]
  3. Bradley L. A., Sweatman A. K., Lovering R. C., Jones A. M., Morgan G., Levinsky R. J., Kinnon C. Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet. 1994 Jan;3(1):79–83. doi: 10.1093/hmg/3.1.79. [DOI] [PubMed] [Google Scholar]
  4. Camps M., Carozzi A., Schnabel P., Scheer A., Parker P. J., Gierschik P. Isozyme-selective stimulation of phospholipase C-beta 2 by G protein beta gamma-subunits. Nature. 1992 Dec 17;360(6405):684–686. doi: 10.1038/360684a0. [DOI] [PubMed] [Google Scholar]
  5. Carozzi A., Camps M., Gierschik P., Parker P. J. Activation of phosphatidylinositol lipid-specific phospholipase C-beta 3 by G-protein beta gamma subunits. FEBS Lett. 1993 Jan 11;315(3):340–342. doi: 10.1016/0014-5793(93)81190-b. [DOI] [PubMed] [Google Scholar]
  6. Crespo P., Xu N., Simonds W. F., Gutkind J. S. Ras-dependent activation of MAP kinase pathway mediated by G-protein beta gamma subunits. Nature. 1994 Jun 2;369(6479):418–420. doi: 10.1038/369418a0. [DOI] [PubMed] [Google Scholar]
  7. Duronio R. J., Gordon J. I., Boguski M. S. Comparative analysis of the beta transducin family with identification of several new members including PWP1, a nonessential gene of Saccharomyces cerevisiae that is divergently transcribed from NMT1. Proteins. 1992 May;13(1):41–56. doi: 10.1002/prot.340130105. [DOI] [PubMed] [Google Scholar]
  8. Dynlacht B. D., Weinzierl R. O., Admon A., Tjian R. The dTAFII80 subunit of Drosophila TFIID contains beta-transducin repeats. Nature. 1993 May 13;363(6425):176–179. doi: 10.1038/363176a0. [DOI] [PubMed] [Google Scholar]
  9. Go N. F., Castle B. E., Barrett R., Kastelein R., Dang W., Mosmann T. R., Moore K. W., Howard M. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med. 1990 Dec 1;172(6):1625–1631. doi: 10.1084/jem.172.6.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gold M. R., Law D. A., DeFranco A. L. Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor. Nature. 1990 Jun 28;345(6278):810–813. doi: 10.1038/345810a0. [DOI] [PubMed] [Google Scholar]
  11. Gregory R. J., Kammermeyer K. L., Vincent W. S., 3rd, Wadsworth S. G. Primary sequence and developmental expression of a novel Drosophila melanogaster src gene. Mol Cell Biol. 1987 Jun;7(6):2119–2127. doi: 10.1128/mcb.7.6.2119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Haslam R. J., Koide H. B., Hemmings B. A. Pleckstrin domain homology. Nature. 1993 May 27;363(6427):309–310. doi: 10.1038/363309b0. [DOI] [PubMed] [Google Scholar]
  13. Heyeck S. D., Berg L. J. Developmental regulation of a murine T-cell-specific tyrosine kinase gene, Tsk. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):669–673. doi: 10.1073/pnas.90.2.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hitoshi Y., Sonoda E., Kikuchi Y., Yonehara S., Nakauchi H., Takatsu K. IL-5 receptor positive B cells, but not eosinophils, are functionally and numerically influenced in mice carrying the X-linked immune defect. Int Immunol. 1993 Sep;5(9):1183–1190. doi: 10.1093/intimm/5.9.1183. [DOI] [PubMed] [Google Scholar]
  15. Inglese J., Freedman N. J., Koch W. J., Lefkowitz R. J. Structure and mechanism of the G protein-coupled receptor kinases. J Biol Chem. 1993 Nov 15;268(32):23735–23738. [PubMed] [Google Scholar]
  16. Jelsema C. L., Axelrod J. Stimulation of phospholipase A2 activity in bovine rod outer segments by the beta gamma subunits of transducin and its inhibition by the alpha subunit. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3623–3627. doi: 10.1073/pnas.84.11.3623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Katz A., Wu D., Simon M. I. Subunits beta gamma of heterotrimeric G protein activate beta 2 isoform of phospholipase C. Nature. 1992 Dec 17;360(6405):686–689. doi: 10.1038/360686a0. [DOI] [PubMed] [Google Scholar]
  18. Kawakami Y., Yao L., Miura T., Tsukada S., Witte O. N., Kawakami T. Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking. Mol Cell Biol. 1994 Aug;14(8):5108–5113. doi: 10.1128/mcb.14.8.5108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Koch C. A., Anderson D., Moran M. F., Ellis C., Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991 May 3;252(5006):668–674. doi: 10.1126/science.1708916. [DOI] [PubMed] [Google Scholar]
  20. Koch W. J., Inglese J., Stone W. C., Lefkowitz R. J. The binding site for the beta gamma subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase. J Biol Chem. 1993 Apr 15;268(11):8256–8260. [PubMed] [Google Scholar]
  21. Kumar S., Matsuzaki T., Yoshida Y., Noda M. Molecular cloning and biological activity of a novel developmentally regulated gene encoding a protein with beta-transducin-like structure. J Biol Chem. 1994 Apr 15;269(15):11318–11326. [PubMed] [Google Scholar]
  22. Lefkowitz R. J. G protein-coupled receptor kinases. Cell. 1993 Aug 13;74(3):409–412. doi: 10.1016/0092-8674(93)80042-d. [DOI] [PubMed] [Google Scholar]
  23. Macias M. J., Musacchio A., Ponstingl H., Nilges M., Saraste M., Oschkinat H. Structure of the pleckstrin homology domain from beta-spectrin. Nature. 1994 Jun 23;369(6482):675–677. doi: 10.1038/369675a0. [DOI] [PubMed] [Google Scholar]
  24. Mano H., Mano K., Tang B., Koehler M., Yi T., Gilbert D. J., Jenkins N. A., Copeland N. G., Ihle J. N. Expression of a novel form of Tec kinase in hematopoietic cells and mapping of the gene to chromosome 5 near Kit. Oncogene. 1993 Feb;8(2):417–424. [PubMed] [Google Scholar]
  25. Mayer B. J., Ren R., Clark K. L., Baltimore D. A putative modular domain present in diverse signaling proteins. Cell. 1993 May 21;73(4):629–630. doi: 10.1016/0092-8674(93)90244-k. [DOI] [PubMed] [Google Scholar]
  26. Melamed I., Wang G., Roifman C. M. Antigen receptor-mediated protein tyrosine kinase activity is regulated by a pertussis toxin-sensitive G protein. J Immunol. 1992 Jul 1;149(1):169–174. [PubMed] [Google Scholar]
  27. Musacchio A., Gibson T., Rice P., Thompson J., Saraste M. The PH domain: a common piece in the structural patchwork of signalling proteins. Trends Biochem Sci. 1993 Sep;18(9):343–348. doi: 10.1016/0968-0004(93)90071-t. [DOI] [PubMed] [Google Scholar]
  28. Müller S., Hekman M., Lohse M. J. Specific enhancement of beta-adrenergic receptor kinase activity by defined G-protein beta and gamma subunits. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10439–10443. doi: 10.1073/pnas.90.22.10439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Narasimhan V., Holowka D., Baird B. A guanine nucleotide-binding protein participates in IgE receptor-mediated activation of endogenous and reconstituted phospholipase A2 in a permeabilized cell system. J Biol Chem. 1990 Jan 25;265(3):1459–1464. [PubMed] [Google Scholar]
  30. Peitsch M. C., Borner C., Tschopp J. Sequence similarity of phospholipase A2 activating protein and the G protein beta-subunits: a new concept of effector protein activation in signal transduction? Trends Biochem Sci. 1993 Aug;18(8):292–293. doi: 10.1016/0968-0004(93)90038-o. [DOI] [PubMed] [Google Scholar]
  31. Pendergast A. M., Muller A. J., Havlik M. H., Maru Y., Witte O. N. BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner. Cell. 1991 Jul 12;66(1):161–171. doi: 10.1016/0092-8674(91)90148-r. [DOI] [PubMed] [Google Scholar]
  32. Pitcher J. A., Inglese J., Higgins J. B., Arriza J. L., Casey P. J., Kim C., Benovic J. L., Kwatra M. M., Caron M. G., Lefkowitz R. J. Role of beta gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors. Science. 1992 Aug 28;257(5074):1264–1267. doi: 10.1126/science.1325672. [DOI] [PubMed] [Google Scholar]
  33. Rawlings D. J., Saffran D. C., Tsukada S., Largaespada D. A., Grimaldi J. C., Cohen L., Mohr R. N., Bazan J. F., Howard M., Copeland N. G. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science. 1993 Jul 16;261(5119):358–361. doi: 10.1126/science.8332901. [DOI] [PubMed] [Google Scholar]
  34. Ron D., Chen C. H., Caldwell J., Jamieson L., Orr E., Mochly-Rosen D. Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):839–843. doi: 10.1073/pnas.91.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Saffran D. C., Parolini O., Fitch-Hilgenberg M. E., Rawlings D. J., Afar D. E., Witte O. N., Conley M. E. Brief report: a point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med. 1994 May 26;330(21):1488–1491. doi: 10.1056/NEJM199405263302104. [DOI] [PubMed] [Google Scholar]
  36. Saouaf S. J., Mahajan S., Rowley R. B., Kut S. A., Fargnoli J., Burkhardt A. L., Tsukada S., Witte O. N., Bolen J. B. Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9524–9528. doi: 10.1073/pnas.91.20.9524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Siliciano J. D., Morrow T. A., Desiderio S. V. itk, a T-cell-specific tyrosine kinase gene inducible by interleukin 2. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11194–11198. doi: 10.1073/pnas.89.23.11194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Simon M. I., Strathmann M. P., Gautam N. Diversity of G proteins in signal transduction. Science. 1991 May 10;252(5007):802–808. doi: 10.1126/science.1902986. [DOI] [PubMed] [Google Scholar]
  39. Smith D. B., Johnson K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. doi: 10.1016/0378-1119(88)90005-4. [DOI] [PubMed] [Google Scholar]
  40. Stephan V., Benhamou M., Gutkind J. S., Robbins K. C., Siraganian R. P. Fc epsilon RI-induced protein tyrosine phosphorylation of pp72 in rat basophilic leukemia cells (RBL-2H3). Evidence for a novel signal transduction pathway unrelated to G protein activation and phosphatidylinositol hydrolysis. J Biol Chem. 1992 Mar 15;267(8):5434–5441. [PubMed] [Google Scholar]
  41. Stephens L., Smrcka A., Cooke F. T., Jackson T. R., Sternweis P. C., Hawkins P. T. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Cell. 1994 Apr 8;77(1):83–93. doi: 10.1016/0092-8674(94)90237-2. [DOI] [PubMed] [Google Scholar]
  42. Tang W. J., Gilman A. G. Type-specific regulation of adenylyl cyclase by G protein beta gamma subunits. Science. 1991 Dec 6;254(5037):1500–1503. doi: 10.1126/science.1962211. [DOI] [PubMed] [Google Scholar]
  43. Thomas J. D., Sideras P., Smith C. I., Vorechovský I., Chapman V., Paul W. E. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science. 1993 Jul 16;261(5119):355–358. doi: 10.1126/science.8332900. [DOI] [PubMed] [Google Scholar]
  44. Touhara K., Inglese J., Pitcher J. A., Shaw G., Lefkowitz R. J. Binding of G protein beta gamma-subunits to pleckstrin homology domains. J Biol Chem. 1994 Apr 8;269(14):10217–10220. [PubMed] [Google Scholar]
  45. Tsukada S., Saffran D. C., Rawlings D. J., Parolini O., Allen R. C., Klisak I., Sparkes R. S., Kubagawa H., Mohandas T., Quan S. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993 Jan 29;72(2):279–290. doi: 10.1016/0092-8674(93)90667-f. [DOI] [PubMed] [Google Scholar]
  46. Vetrie D., Vorechovský I., Sideras P., Holland J., Davies A., Flinter F., Hammarström L., Kinnon C., Levinsky R., Bobrow M. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226–233. doi: 10.1038/361226a0. [DOI] [PubMed] [Google Scholar]
  47. Wickman K. D., Iñiguez-Lluhl J. A., Davenport P. A., Taussig R., Krapivinsky G. B., Linder M. E., Gilman A. G., Clapham D. E. Recombinant G-protein beta gamma-subunits activate the muscarinic-gated atrial potassium channel. Nature. 1994 Mar 17;368(6468):255–257. doi: 10.1038/368255a0. [DOI] [PubMed] [Google Scholar]
  48. Wu D., Katz A., Simon M. I. Activation of phospholipase C beta 2 by the alpha and beta gamma subunits of trimeric GTP-binding protein. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5297–5301. doi: 10.1073/pnas.90.11.5297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yoon H. S., Hajduk P. J., Petros A. M., Olejniczak E. T., Meadows R. P., Fesik S. W. Solution structure of a pleckstrin-homology domain. Nature. 1994 Jun 23;369(6482):672–675. doi: 10.1038/369672a0. [DOI] [PubMed] [Google Scholar]
  50. de Weers M., Mensink R. G., Kraakman M. E., Schuurman R. K., Hendriks R. W. Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. Hum Mol Genet. 1994 Jan;3(1):161–166. doi: 10.1093/hmg/3.1.161. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES