Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1996 Sep 2;15(17):4537–4546.

Activation of a human Ste20-like kinase by oxidant stress defines a novel stress response pathway.

C M Pombo 1, J V Bonventre 1, A Molnar 1, J Kyriakis 1, T Force 1
PMCID: PMC452183  PMID: 8887545

Abstract

Mammalian homologs of the yeast protein kinase, Sterile 20 (Ste20), can be divided into two groups based on their regulation and structure. The first group, which includes PAK1, is regulated by Rac and Cdc42Hs, and activators have been identified. In contrast, very little is known about activators, regulatory mechanisms or physiological roles of the other group, which consists of GC kinase and MST1. We have identified a human Ste20-like kinase from the GC kinase group, SOK-1 (Ste20/oxidant stress response kinase-1), which is activated by oxidant stress. The kinase is activated by autophosphorylation and is markedly inhibited by its non-catalytic C-terminal region. SOK-1 is activated 3- to 7-fold by reactive oxygen intermediates, but is not activated by growth factors, alkylating agents, cytokines or environmental stresses including heat shock and osmolar stress. Although these data place SOK-1 on a stress response pathway, SOK-1, unlike GC kinase and PAK1, does not activate either of the stress-activated MAP kinase cascades (p38 and SAPKs). SOK-1 is the first mammalian Ste20-like kinase which is activated by cellular stress, and the activation is relatively specific for oxidant stress. Since SOK-1 does not activate any of the known MAP kinase cascades, its activation defines a novel stress response pathway which is likely to include a unique stress-activated MAP kinase cascade.

Full text

PDF

Images in this article

4539Image
on p.4539
4539Image
on p.4539
4540Image
on p.4540
4541Image
on p.4541
4541Image
on p.4541
4542Image
on p.4542
4542Image
on p.4542

Selected References

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

  1. Ansorge W., Pepperkok R. Performance of an automated system for capillary microinjection into living cells. J Biochem Biophys Methods. 1988 Aug;16(4):283–292. doi: 10.1016/0165-022x(88)90062-0. [DOI] [PubMed] [Google Scholar]
  2. Brown D., Lydon J., McLaughlin M., Stuart-Tilley A., Tyszkowski R., Alper S. Antigen retrieval in cryostat tissue sections and cultured cells by treatment with sodium dodecyl sulfate (SDS). Histochem Cell Biol. 1996 Apr;105(4):261–267. doi: 10.1007/BF01463929. [DOI] [PubMed] [Google Scholar]
  3. Bruder J. T., Heidecker G., Rapp U. R. Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase. Genes Dev. 1992 Apr;6(4):545–556. doi: 10.1101/gad.6.4.545. [DOI] [PubMed] [Google Scholar]
  4. Burbelo P. D., Drechsel D., Hall A. A conserved binding motif defines numerous candidate target proteins for both Cdc42 and Rac GTPases. J Biol Chem. 1995 Dec 8;270(49):29071–29074. doi: 10.1074/jbc.270.49.29071. [DOI] [PubMed] [Google Scholar]
  5. Chen J., Martin B. L., Brautigan D. L. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science. 1992 Aug 28;257(5074):1261–1264. doi: 10.1126/science.1325671. [DOI] [PubMed] [Google Scholar]
  6. Creasy C. L., Chernoff J. Cloning and characterization of a human protein kinase with homology to Ste20. J Biol Chem. 1995 Sep 15;270(37):21695–21700. doi: 10.1074/jbc.270.37.21695. [DOI] [PubMed] [Google Scholar]
  7. Cvrcková F., De Virgilio C., Manser E., Pringle J. R., Nasmyth K. Ste20-like protein kinases are required for normal localization of cell growth and for cytokinesis in budding yeast. Genes Dev. 1995 Aug 1;9(15):1817–1830. doi: 10.1101/gad.9.15.1817. [DOI] [PubMed] [Google Scholar]
  8. Elion E. A. Ste5: a meeting place for MAP kinases and their associates. Trends Cell Biol. 1995 Aug;5(8):322–327. doi: 10.1016/s0962-8924(00)89055-8. [DOI] [PubMed] [Google Scholar]
  9. Friesen H., Lunz R., Doyle S., Segall J. Mutation of the SPS1-encoded protein kinase of Saccharomyces cerevisiae leads to defects in transcription and morphology during spore formation. Genes Dev. 1994 Sep 15;8(18):2162–2175. doi: 10.1101/gad.8.18.2162. [DOI] [PubMed] [Google Scholar]
  10. Galcheva-Gargova Z., Dérijard B., Wu I. H., Davis R. J. An osmosensing signal transduction pathway in mammalian cells. Science. 1994 Aug 5;265(5173):806–808. doi: 10.1126/science.8047888. [DOI] [PubMed] [Google Scholar]
  11. Guan K. L., Dixon J. E. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Anal Biochem. 1991 Feb 1;192(2):262–267. doi: 10.1016/0003-2697(91)90534-z. [DOI] [PubMed] [Google Scholar]
  12. Han J., Lee J. D., Bibbs L., Ulevitch R. J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994 Aug 5;265(5173):808–811. doi: 10.1126/science.7914033. [DOI] [PubMed] [Google Scholar]
  13. Hanks S. K., Quinn A. M. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 1991;200:38–62. doi: 10.1016/0076-6879(91)00126-h. [DOI] [PubMed] [Google Scholar]
  14. Herskowitz I. MAP kinase pathways in yeast: for mating and more. Cell. 1995 Jan 27;80(2):187–197. doi: 10.1016/0092-8674(95)90402-6. [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. Hockenbery D. M., Oltvai Z. N., Yin X. M., Milliman C. L., Korsmeyer S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. doi: 10.1016/0092-8674(93)80066-n. [DOI] [PubMed] [Google Scholar]
  17. Katz P., Whalen G., Kehrl J. H. Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center. J Biol Chem. 1994 Jun 17;269(24):16802–16809. [PubMed] [Google Scholar]
  18. Kharbanda S., Ren R., Pandey P., Shafman T. D., Feller S. M., Weichselbaum R. R., Kufe D. W. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature. 1995 Aug 31;376(6543):785–788. doi: 10.1038/376785a0. [DOI] [PubMed] [Google Scholar]
  19. Kharbanda S., Saleem A., Shafman T., Emoto Y., Taneja N., Rubin E., Weichselbaum R., Woodgett J., Avruch J., Kyriakis J. Ionizing radiation stimulates a Grb2-mediated association of the stress-activated protein kinase with phosphatidylinositol 3-kinase. J Biol Chem. 1995 Aug 11;270(32):18871–18874. doi: 10.1074/jbc.270.32.18871. [DOI] [PubMed] [Google Scholar]
  20. Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem. 1991 Oct 25;266(30):19867–19870. [PubMed] [Google Scholar]
  21. Krisak L., Strich R., Winters R. S., Hall J. P., Mallory M. J., Kreitzer D., Tuan R. S., Winter E. SMK1, a developmentally regulated MAP kinase, is required for spore wall assembly in Saccharomyces cerevisiae. Genes Dev. 1994 Sep 15;8(18):2151–2161. doi: 10.1101/gad.8.18.2151. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  24. Leberer E., Dignard D., Harcus D., Thomas D. Y., Whiteway M. The protein kinase homologue Ste20p is required to link the yeast pheromone response G-protein beta gamma subunits to downstream signalling components. EMBO J. 1992 Dec;11(13):4815–4824. doi: 10.1002/j.1460-2075.1992.tb05587.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Levin D. E., Errede B. The proliferation of MAP kinase signaling pathways in yeast. Curr Opin Cell Biol. 1995 Apr;7(2):197–202. doi: 10.1016/0955-0674(95)80028-x. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Manser E., Leung T., Salihuddin H., Zhao Z. S., Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994 Jan 6;367(6458):40–46. doi: 10.1038/367040a0. [DOI] [PubMed] [Google Scholar]
  28. Martin G. A., Bollag G., McCormick F., Abo A. A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. EMBO J. 1995 May 1;14(9):1970–1978. doi: 10.1002/j.1460-2075.1995.tb07189.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Morooka H., Bonventre J. V., Pombo C. M., Kyriakis J. M., Force T. Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter. J Biol Chem. 1995 Dec 15;270(50):30084–30092. doi: 10.1074/jbc.270.50.30084. [DOI] [PubMed] [Google Scholar]
  30. Pagano M., Theodoras A. M., Tam S. W., Draetta G. F. Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Dev. 1994 Jul 15;8(14):1627–1639. doi: 10.1101/gad.8.14.1627. [DOI] [PubMed] [Google Scholar]
  31. Polverino A., Frost J., Yang P., Hutchison M., Neiman A. M., Cobb M. H., Marcus S. Activation of mitogen-activated protein kinase cascades by p21-activated protein kinases in cell-free extracts of Xenopus oocytes. J Biol Chem. 1995 Nov 3;270(44):26067–26070. doi: 10.1074/jbc.270.44.26067. [DOI] [PubMed] [Google Scholar]
  32. Pombo C. M., Bonventre J. V., Avruch J., Woodgett J. R., Kyriakis J. M., Force T. The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. J Biol Chem. 1994 Oct 21;269(42):26546–26551. [PubMed] [Google Scholar]
  33. Pombo C. M., Kehrl J. H., Sánchez I., Katz P., Avruch J., Zon L. I., Woodgett J. R., Force T., Kyriakis J. M. Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature. 1995 Oct 26;377(6551):750–754. doi: 10.1038/377750a0. [DOI] [PubMed] [Google Scholar]
  34. Radler-Pohl A., Sachsenmaier C., Gebel S., Auer H. P., Bruder J. T., Rapp U., Angel P., Rahmsdorf H. J., Herrlich P. UV-induced activation of AP-1 involves obligatory extranuclear steps including Raf-1 kinase. EMBO J. 1993 Mar;12(3):1005–1012. doi: 10.1002/j.1460-2075.1993.tb05741.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rouse J., Cohen P., Trigon S., Morange M., Alonso-Llamazares A., Zamanillo D., Hunt T., Nebreda A. R. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell. 1994 Sep 23;78(6):1027–1037. doi: 10.1016/0092-8674(94)90277-1. [DOI] [PubMed] [Google Scholar]
  36. Russo T., Zambrano N., Esposito F., Ammendola R., Cimino F., Fiscella M., Jackman J., O'Connor P. M., Anderson C. W., Appella E. A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress. J Biol Chem. 1995 Dec 8;270(49):29386–29391. doi: 10.1074/jbc.270.49.29386. [DOI] [PubMed] [Google Scholar]
  37. Sánchez I., Hughes R. T., Mayer B. J., Yee K., Woodgett J. R., Avruch J., Kyriakis J. M., Zon L. I. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. doi: 10.1038/372794a0. [DOI] [PubMed] [Google Scholar]
  38. Thor H., Smith M. T., Hartzell P., Bellomo G., Jewell S. A., Orrenius S. The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells. J Biol Chem. 1982 Oct 25;257(20):12419–12425. [PubMed] [Google Scholar]
  39. Witzgall R., O'Leary E., Gessner R., Ouellette A. J., Bonventre J. V. Kid-1, a putative renal transcription factor: regulation during ontogeny and in response to ischemia and toxic injury. Mol Cell Biol. 1993 Mar;13(3):1933–1942. doi: 10.1128/mcb.13.3.1933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wu C., Whiteway M., Thomas D. Y., Leberer E. Molecular characterization of Ste20p, a potential mitogen-activated protein or extracellular signal-regulated kinase kinase (MEK) kinase kinase from Saccharomyces cerevisiae. J Biol Chem. 1995 Jul 7;270(27):15984–15992. doi: 10.1074/jbc.270.27.15984. [DOI] [PubMed] [Google Scholar]
  41. Zhang S., Han J., Sells M. A., Chernoff J., Knaus U. G., Ulevitch R. J., Bokoch G. M. Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem. 1995 Oct 13;270(41):23934–23936. doi: 10.1074/jbc.270.41.23934. [DOI] [PubMed] [Google Scholar]
  42. Zhou G., Bao Z. Q., Dixon J. E. Components of a new human protein kinase signal transduction pathway. J Biol Chem. 1995 May 26;270(21):12665–12669. doi: 10.1074/jbc.270.21.12665. [DOI] [PubMed] [Google Scholar]
  43. 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