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

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.

Isolation and characterization of a novel serine threonine kinase gene on chromosome 3p22-21.3

“…However, SOK1 is not involved in the generalized stress response pathway that is stimulated by growth factors, alkylating agents, cytokines, or environmental situations such as heat shock and osmolar stress. It is activated relatively specifically by oxidant stress, although it does not activate any of the known mitogen activated protein (MAP) kinase cascades (Creasy and Sheriff 1995;Pombe et al 1996). MST1, although it is homologous to a member of a yeast mitogen activated protein kinase (MAPK) cascade, is not involved in regulating any mammalian MAPK pathway; this kinase potentially regulates a novel signaling cascade (Creasy et al 1996).…”

Protein Phosphatase 2C Acts Independently of Stress-activated Kinase Cascade to Regulate the Stress Response in Fission Yeast

“…These observations suggest that some cross-talk may exist between stress-activated kinase cascades. Recently, the cloning of a novel protein kinase gene, SOK1, implicated in stress response has been reported in S. cerevisiae (30). Although Sok1p is only activated by oxidative stress, it appears that several kinase cascades can contribute to the stress response.…”

From receptors to stress-activated MAP kinases

“…In addition, genetic evidence from yeast and¯ies suggests that a group of kinases which appear to function upstream of MAPKKKs may exist in certain MAPK modules (Widmann et al, 1999;Kyriakis, 1999), despite the lack of direct biochemical evidence that these kinases activate MAPKKK by phosphorylation. Thus, at least 14 di erent but structurally related kinases in this group are suggested to function as mammalian MAPKKKKs, including PAK1, 2, 3 and 4 (Manser et al, 1994;Knaus et al, 1995;Abo, 1998), GCK (Katz et al, 1994), GCKR/KHS (Shi and Kehrl, 1997;Tung and Blenis, 1997), GLK , HPK1 (Kiefer et al, 1996;Hu et al, 1996), NIK (Nck-interacting kinase)/HGK (Su et al 1997;Yao et al 1999), SOK1 (previously called UK-1; Pombo et al, 1996), Krs-1 (Taylor et al, 1996), MST1/Krs-2(Creasy and Cherno , 1995; Taylor et al, 1996), MST3 (Schinkmann and Blenis, 1997) and LOK (Kuramochi et al, 1997). Most of the MAPKKKKs, but not SOK1, Krs-1, MST3 and LOK, can activate JNK by overexpression.…”