Activation of a human Ste20-like kinase by oxidant stress defines a novel stress response pathway.
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.
Cardiac Research Unit of the Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, USA.
C M
CM
Pombo
J V
JV
Bonventre
A
A
Molnar
J
J
Kyriakis
T
T
Force
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid
D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; D017346:Protein Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C078754:STE20 protein, S cerevisiae