Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Concentration-dependent positive and negative regulation of a MAP kinase by a MAP kinase kinase

Oncogene volume 18, pages 6647–6657 (1999)Cite this article

Abstract

There are at least three distinct MAP kinase signaling modules in mammalian cells, distinguished by the family of kinases (Erk, SAPK/JNK, or p38) that is ultimately activated. Many input signals activate multiple MAP kinase cascades, and the mechanisms that control the specificity of signal output are not well understood. We show that SEK1/MKK4, a MAP kinase kinase proposed to activate SAPK/JNK, is a very potent inhibitor of p54 SAPKβ/JNK3 both in vitro and in vivo if present at equimolar or higher ratios. In contrast SEK can activate SAPK when present in substoichiometric amounts, but this activation is slow, consistent with the rate-limiting step in activation being the dissociation of an inactive SEK : SAPK complex. The N-terminal unique region of SEK is both necessary and partially sufficient for inhibition of SAPK, and is also necessary for activation of SAPK by SEK in vitro. We have also used the p38 MAP kinase and its activator MKK6 to examine the regulatory relationships among different kinases involved in stress responses. We show using purified kinases that inhibitory activity is specific for the combination of SEK and SAPK: SEK can activate but not inhibit p38, and MKK6 can activate but not inhibit SAPKβ and p38. These results reveal a potential mechanism for regulating stress-activated kinases, adding to a growing body of evidence suggesting that MAP kinases are controlled by relatively stable interactions with their activators.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Bardwell L, Cook JG, Chang EC, Cairns BR and Thorner J. . 1996 Mol. Cell. Biol. 16: 3637–3650.

  • Bardwell L and Thorner J. . 1996 Trends Biochem. Sci. 21: 373–374.

  • Canagarajah BJ, Khokhlatchev A, Cobb MH and Goldsmith EJ. . 1997 Cell 90: 859–869.

  • Chen RH, Sarnecki C and Blenis J. . 1992 Mol. Cell. Biol. 12: 915–927.

  • Choi K-Y, Satterberg B, Lyons DM and Elion EA. . 1994 Cell 78: 499–512.

  • Clark-Lewis I, Sanghera JS and Pelech SL. . 1991 J. Biol. Chem. 266: 15180–15184.

  • Cobb MH and Goldsmith EJ. . 1995 J. Biol. Chem. 270: 14843–14846.

  • Cuenda A, Alonso G, Morrice N, Jones M, Meier R, Cohen P and Nebreda AR. . 1996 EMBO J. 15: 4156–4164.

  • Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M and Davis RJ. . 1994 Cell 76: 1025–1037.

  • Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevich RJ and Davis RJ. . 1995 Science 267: 682–685.

  • Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL and Davis RJ. . 1997 Science 277: 693–696.

  • Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J and Saklatvala J. . 1994 Cell 78: 1039–1049.

  • Fukuda M, Gotoh Y and Nishida E. . 1997 EMBO J. 16: 1901–1908.

  • Ganiatsas S, Kwee L, Fujiwara Y, Perkins A, Ikeda T, Labow MA and Zon LI. . 1998 Proc. Natl. Acad. Sci. USA 95: 6881–6886.

  • Han J, Lee J-D, Bibbs L and Ulevich RJ. . 1994 Science 265: 808–811.

  • Han J, Lee JD, Jiang Y, Li Z, Feng L and Ulevich RJ. . 1996 J. Biol. Chem. 271: 2886–2891.

  • Holland PM, Suzanne M, Campbell JS, Noselli S and Cooper JA. . 1997 J. Biol. Chem. 272: 24994–24998.

  • Johnson LN, Noble MEM and Owen DJ. . 1996 Cell 85: 149–158.

  • Khokhlatchev AV, Canagarajah B, Wilsbacher J, Robinson M, Atkinson M, Goldsmith E and Cobb MH. . 1998 Cell 93: 605–615.

  • Kyriakis JM and Avruch J. . 1996 BioEssays 18: 567–577.

  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J and Woodgett JR. . 1994 Nature 369: 156–160.

  • Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, E SJ, McLaughlin MM, Siemens IR, Fisher SM, Livi GP, Wjite JR, Adams JL and Young PR. . 1994 Nature 372: 739–746.

  • Lenormand P, Sardet C, Pages G, L'Allemain G, Brunet A and Pouyssegur J. . 1993 J. Cell Biol. 122: 1079–1088.

  • Lewis TS, Shapiro PS and Ahn NG. . 1998 Adv. Cancer Res. 74: 49–139.

  • Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL and Karin M. . 1995 Science 268: 286–290.

  • Marcus S, Polverino A, Barr M and Wigler M. . 1994 Proc. Natl. Acad. Sci. USA 91: 7762–7766.

  • Mendelson KG, Contois L-R, Tevosian SG, Davis RJ and Paulson KE. . 1996 Proc. Natl. Acad. Sci. USA 93: 12908–12913.

  • Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E and Hagiwara M. . 1996a J. Biol. Chem. 271: 13675–13679.

  • Moriguchi T, Toyoshima F, Gotoh Y, Iwamatsu A, Irie K, Mori E, Kuroyanagi N, Hagiwara M, Matsumoto K and Nishida E. . 1996b J. Biol. Chem. 271: 26981–26988.

  • Moriguchi T, Toyoshima F, Masuyama N, Hanafusa H, Gotoh Y and Nishida E. . 1997 EMBO J. 16: 7045–7053.

  • Nishina H, Fischer KD, Radvanyi L, Shahinian A, Hakem R, Rubie EA, Bernstein A, Mak TW, Woodgett JR and Penninger JM. . 1997 Nature 385: 350–353.

  • Paul A, Wilson S, Belham CH, Robinson CJ, Scott PH, Gould GW and Plevin R. . 1997 Cell Signal. 9: 403–410.

  • Pelech SL. . 1996 Curr. Biol. 6: 551–554.

  • Printen JA and Sprague Jr, GF. . 1994 Genetics 138: 609–619.

  • Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevich RJ and Davis RJ. . 1995 J. Biol. Chem. 270: 7420–7426.

  • Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B and Davis RJ. . 1996 Mol. Cell. Biol. 16: 1247–1255.

  • Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T and Nebreda AR. . 1994 Cell 78: 1027–1037.

  • Sanchez I, Hughes RT, Mayer BJ, Yee K, Woodgett JR, Avruch J, Kyriakis JM and Zon LI. . 1994 Nature 372: 794–798.

  • Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A and Weber MJ. . 1998 Science 281: 1668–1671.

  • Seth A, Gonzalez FA, Gupta S, Raden DL and Davis RJ. . 1992 J. Biol. Chem. 267: 24796–24804.

  • Shim J, Lee H, Park J, Kim H and Choi E-J. . 1996 Nature 381: 804–807.

  • Songyang Z, Lu KP, Kwon YT, Tsai L-H, Filhol O, Cochet C, Brickey DA, Soderling TR, Bartleson C, Graves DJ, DeMaggio AJ, Hoekstra MF, Blenis J, Hunter T and Cantley LC. . 1996 Mol. Cell. Biol. 16: 6486–6493.

  • Stein B, Brady H, Yang MX, Young DB and Barbosa MS. . 1996 J. Biol. Chem. 271: 11427–11433.

  • Tanaka M, Gupta R and Mayer BJ. . 1995 Mol. Cell. Biol. 15: 6829–6837.

  • Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T and Davis RJ. . 1997 Proc. Natl. Acad. Sci. USA 94: 7337–7343.

  • Waskiewicz AJ and Cooper JA. . 1995 Curr. Opin. Cell Biol. 7: 798–805.

  • Whitmarsh AJ, Cavanagh J, Tournier C, Yasuda J and Davis RJ. . 1998 Science 281: 1671–1674.

  • Wu Z, Wu J, Jacinto E and Karin M. . 1997 Mol. Cell. Biol. 17: 7407–7416.

  • Yang D, Tournier C, Wysk M, Lu H-T, Xu J, Davis RJ and Flavell RA. . 1997 Proc. Natl. Acad. Sci. USA 94: 3004–3009.

  • Yao Z, Diener K, Wang XS, Zukowski M, Matsumoto G, Zhou G, Mo R, Sasaki T, Nishina H, Hui CC, Tan TH, Woodgett JP and Penninger JM. . 1997 J. Biol. Chem. 272: 32378–32383.

  • Yashar BM, Kelley C, Yee K, Errede B and Zon LI. . 1993 Mol. Cell. Biol. 13: 5738–5748.

  • Zanke BW, Rubie EA, Winnett E, Chan J, Randall S, Parsons M, Boudreau K, McInnis M, Yan M, Templeton DJ and Woodgett JR. . 1996 J. Biol. Chem. 271: 29876–29881.

Download references

Acknowledgements

We thank B Yashar and B Errede for providing the XMek3 PCR fragment, E Marieb for technical assistance, and J Blenis, A Dutta and E Elion for critical comments on this manuscript. LI Zon is an Associate Investigator and BJ Mayer is an Assistant Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital, 320 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    Mark W Kieran, Brenda Vail & Leonard I Zon

  2. Department of Microbiology and Molecular Genetics, Harvard Medical School, Howard Hughes Medical Institute, Children's Hospital, 320 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    Steve Katz & Bruce J Mayer

Authors
  1. Mark W Kieran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steve Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brenda Vail
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonard I Zon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruce J Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kieran, M., Katz, S., Vail, B. et al. Concentration-dependent positive and negative regulation of a MAP kinase by a MAP kinase kinase. Oncogene 18, 6647–6657 (1999). https://doi.org/10.1038/sj.onc.1203057

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203057

Keywords

This article is cited by

Search

Advanced search

Quick links