Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 Mar 16;17(6):1740–1749. doi: 10.1093/emboj/17.6.1740

Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1.

S H Yang 1, A J Whitmarsh 1, R J Davis 1, A D Sharrocks 1
PMCID: PMC1170521  PMID: 9501095

Abstract

The activation of MAP kinase (MAPK) signal transduction pathways results in the phosphorylation of transcription factors by the terminal kinases in these cascades. Different pathways are activated by mitogenic and stress stimuli, which lead to the activation of distinct groups of target proteins. The ETS-domain transcription factor Elk-1 is a substrate for three distinct classes of MAPKs. Elk-1 contains a targeting domain, the D-domain, which is distinct from the phosphoacceptor motifs and is required for efficient phosphorylation and activation by the ERK MAPKs. In this study, we demonstrate that members of the JNK subfamily of MAPKs are also targeted to Elk-1 by this domain. Targeting via this domain is essential for the efficient and rapid phosphorylation and activation of Elk-1 both in vitro and in vivo. The ERK and JNK MAPKs use overlapping yet distinct determinants in the D-domain for targeting to Elk-1. In contrast, members of the p38 subfamily of MAPKs are not targeted to Elk-1 via this domain. Our data therefore demonstrate that different classes of MAPKs exhibit differential requirements for targeting to Elk-1.

Full Text

The Full Text of this article is available as a PDF (511.4 KB).

Selected References

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

  1. Bocco J. L., Bahr A., Goetz J., Hauss C., Kallunki T., Kedinger C., Chatton B. In vivo association of ATFa with JNK/SAP kinase activities. Oncogene. 1996 May 2;12(9):1971–1980. [PubMed] [Google Scholar]
  2. Cavigelli M., Dolfi F., Claret F. X., Karin M. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J. 1995 Dec 1;14(23):5957–5964. doi: 10.1002/j.1460-2075.1995.tb00284.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chow C. W., Rincón M., Cavanagh J., Dickens M., Davis R. J. Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science. 1997 Nov 28;278(5343):1638–1641. doi: 10.1126/science.278.5343.1638. [DOI] [PubMed] [Google Scholar]
  4. Cuenda A., Cohen P., Buée-Scherrer V., Goedert M. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. 1997 Jan 15;16(2):295–305. doi: 10.1093/emboj/16.2.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dai T., Rubie E., Franklin C. C., Kraft A., Gillespie D. A., Avruch J., Kyriakis J. M., Woodgett J. R. Stress-activated protein kinases bind directly to the delta domain of c-Jun in resting cells: implications for repression of c-Jun function. Oncogene. 1995 Mar 2;10(5):849–855. [PubMed] [Google Scholar]
  6. Dickens M., Rogers J. S., Cavanagh J., Raitano A., Xia Z., Halpern J. R., Greenberg M. E., Sawyers C. L., Davis R. J. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science. 1997 Aug 1;277(5326):693–696. doi: 10.1126/science.277.5326.693. [DOI] [PubMed] [Google Scholar]
  7. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  8. Enslen H., Raingeaud J., Davis R. J. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998 Jan 16;273(3):1741–1748. doi: 10.1074/jbc.273.3.1741. [DOI] [PubMed] [Google Scholar]
  9. Gille H., Strahl T., Shaw P. E. Activation of ternary complex factor Elk-1 by stress-activated protein kinases. Curr Biol. 1995 Oct 1;5(10):1191–1200. doi: 10.1016/s0960-9822(95)00235-1. [DOI] [PubMed] [Google Scholar]
  10. Goedert M., Cuenda A., Craxton M., Jakes R., Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997 Jun 16;16(12):3563–3571. doi: 10.1093/emboj/16.12.3563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gupta S., Barrett T., Whitmarsh A. J., Cavanagh J., Sluss H. K., Dérijard B., Davis R. J. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996 Jun 3;15(11):2760–2770. [PMC free article] [PubMed] [Google Scholar]
  12. Gupta S., Campbell D., Dérijard B., Davis R. J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. doi: 10.1126/science.7824938. [DOI] [PubMed] [Google Scholar]
  13. Gupta S., Davis R. J. MAP kinase binds to the NH2-terminal activation domain of c-Myc. FEBS Lett. 1994 Oct 24;353(3):281–285. doi: 10.1016/0014-5793(94)01052-8. [DOI] [PubMed] [Google Scholar]
  14. Han J., Jiang Y., Li Z., Kravchenko V. V., Ulevitch R. J. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature. 1997 Mar 20;386(6622):296–299. doi: 10.1038/386296a0. [DOI] [PubMed] [Google Scholar]
  15. Hibi M., Lin A., Smeal T., Minden A., Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. doi: 10.1101/gad.7.11.2135. [DOI] [PubMed] [Google Scholar]
  16. Janknecht R., Hunter T. Activation of the Sap-1a transcription factor by the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase. J Biol Chem. 1997 Feb 14;272(7):4219–4224. doi: 10.1074/jbc.272.7.4219. [DOI] [PubMed] [Google Scholar]
  17. Janknecht R., Hunter T. Convergence of MAP kinase pathways on the ternary complex factor Sap-1a. EMBO J. 1997 Apr 1;16(7):1620–1627. doi: 10.1093/emboj/16.7.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jiang Y., Chen C., Li Z., Guo W., Gegner J. A., Lin S., Han J. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996 Jul 26;271(30):17920–17926. doi: 10.1074/jbc.271.30.17920. [DOI] [PubMed] [Google Scholar]
  19. Kallunki T., Deng T., Hibi M., Karin M. c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions. Cell. 1996 Nov 29;87(5):929–939. doi: 10.1016/s0092-8674(00)81999-6. [DOI] [PubMed] [Google Scholar]
  20. Kallunki T., Su B., Tsigelny I., Sluss H. K., Dérijard B., Moore G., Davis R., Karin M. JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 1994 Dec 15;8(24):2996–3007. doi: 10.1101/gad.8.24.2996. [DOI] [PubMed] [Google Scholar]
  21. Kyriakis J. M., Banerjee P., Nikolakaki E., Dai T., Rubie E. A., Ahmad M. F., Avruch J., Woodgett J. R. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. doi: 10.1038/369156a0. [DOI] [PubMed] [Google Scholar]
  22. Lechner C., Zahalka M. A., Giot J. F., Møller N. P., Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4355–4359. doi: 10.1073/pnas.93.9.4355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Livingstone C., Patel G., Jones N. ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 1995 Apr 18;14(8):1785–1797. doi: 10.1002/j.1460-2075.1995.tb07167.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mao C., Ray-Gallet D., Tavitian A., Moreau-Gachelin F. Differential phosphorylations of Spi-B and Spi-1 transcription factors. Oncogene. 1996 Feb 15;12(4):863–873. [PubMed] [Google Scholar]
  25. Price M. A., Cruzalegui F. H., Treisman R. The p38 and ERK MAP kinase pathways cooperate to activate Ternary Complex Factors and c-fos transcription in response to UV light. EMBO J. 1996 Dec 2;15(23):6552–6563. [PMC free article] [PubMed] [Google Scholar]
  26. Raingeaud J., Gupta S., Rogers J. S., Dickens M., Han J., Ulevitch R. J., Davis R. J. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995 Mar 31;270(13):7420–7426. doi: 10.1074/jbc.270.13.7420. [DOI] [PubMed] [Google Scholar]
  27. Robinson M. J., Cobb M. H. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997 Apr;9(2):180–186. doi: 10.1016/s0955-0674(97)80061-0. [DOI] [PubMed] [Google Scholar]
  28. Sadowski I., Ptashne M. A vector for expressing GAL4(1-147) fusions in mammalian cells. Nucleic Acids Res. 1989 Sep 25;17(18):7539–7539. doi: 10.1093/nar/17.18.7539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Seth A., Gonzalez F. A., Gupta S., Raden D. L., Davis R. J. Signal transduction within the nucleus by mitogen-activated protein kinase. J Biol Chem. 1992 Dec 5;267(34):24796–24804. [PubMed] [Google Scholar]
  30. Shore P., Bisset L., Lakey J., Waltho J. P., Virden R., Sharrocks A. D. Characterization of the Elk-1 ETS DNA-binding domain. J Biol Chem. 1995 Mar 17;270(11):5805–5811. doi: 10.1074/jbc.270.11.5805. [DOI] [PubMed] [Google Scholar]
  31. Shore P., Sharrocks A. D. The transcription factors Elk-1 and serum response factor interact by direct protein-protein contacts mediated by a short region of Elk-1. Mol Cell Biol. 1994 May;14(5):3283–3291. doi: 10.1128/mcb.14.5.3283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shore P., Whitmarsh A. J., Bhaskaran R., Davis R. J., Waltho J. P., Sharrocks A. D. Determinants of DNA-binding specificity of ETS-domain transcription factors. Mol Cell Biol. 1996 Jul;16(7):3338–3349. doi: 10.1128/mcb.16.7.3338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sluss H. K., Barrett T., Dérijard B., Davis R. J. Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol. 1994 Dec;14(12):8376–8384. doi: 10.1128/mcb.14.12.8376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stein B., Yang M. X., Young D. B., Janknecht R., Hunter T., Murray B. W., Barbosa M. S. p38-2, a novel mitogen-activated protein kinase with distinct properties. J Biol Chem. 1997 Aug 1;272(31):19509–19517. doi: 10.1074/jbc.272.31.19509. [DOI] [PubMed] [Google Scholar]
  35. Strahl T., Gille H., Shaw P. E. Selective response of ternary complex factor Sap1a to different mitogen-activated protein kinase subgroups. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11563–11568. doi: 10.1073/pnas.93.21.11563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Treisman R. Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol. 1996 Apr;8(2):205–215. doi: 10.1016/s0955-0674(96)80067-6. [DOI] [PubMed] [Google Scholar]
  37. Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994 Feb;4(1):96–101. doi: 10.1016/0959-437x(94)90097-3. [DOI] [PubMed] [Google Scholar]
  38. Wang X. S., Diener K., Manthey C. L., Wang S., Rosenzweig B., Bray J., Delaney J., Cole C. N., Chan-Hui P. Y., Mantlo N. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. J Biol Chem. 1997 Sep 19;272(38):23668–23674. doi: 10.1074/jbc.272.38.23668. [DOI] [PubMed] [Google Scholar]
  39. Wang X. Z., Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science. 1996 May 31;272(5266):1347–1349. doi: 10.1126/science.272.5266.1347. [DOI] [PubMed] [Google Scholar]
  40. Waskiewicz A. J., Flynn A., Proud C. G., Cooper J. A. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997 Apr 15;16(8):1909–1920. doi: 10.1093/emboj/16.8.1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Whitmarsh A. J., Davis R. J. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl) 1996 Oct;74(10):589–607. doi: 10.1007/s001090050063. [DOI] [PubMed] [Google Scholar]
  42. Whitmarsh A. J., Shore P., Sharrocks A. D., Davis R. J. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995 Jul 21;269(5222):403–407. doi: 10.1126/science.7618106. [DOI] [PubMed] [Google Scholar]
  43. Whitmarsh A. J., Yang S. H., Su M. S., Sharrocks A. D., Davis R. J. Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol. 1997 May;17(5):2360–2371. doi: 10.1128/mcb.17.5.2360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yang S. H., Yates P. R., Whitmarsh A. J., Davis R. J., Sharrocks A. D. The Elk-1 ETS-domain transcription factor contains a mitogen-activated protein kinase targeting motif. Mol Cell Biol. 1998 Feb;18(2):710–720. doi: 10.1128/mcb.18.2.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. van Dam H., Wilhelm D., Herr I., Steffen A., Herrlich P., Angel P. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J. 1995 Apr 18;14(8):1798–1811. doi: 10.1002/j.1460-2075.1995.tb07168.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES