Stress-activated protein kinases SAPKs

A second family of MAPKs is referred to as stress-activated protein kinases (SAPKs) [3,14,15]. This includes JNKs, or Jun kinases, named originally for their phosphorylation of the transcription factor c-Jun. SAPKs were first identified in peripheral tissues on the basis of their activation in response to cellular forms of stress, which include X-ray irradiation and osmotic stress. More recently, they have been demonstrated to be activated in brain by several cytokines as well as by synaptic activity [16]. As shown in Figure 23-3, SAPKs are activated by SAPK kinases (SEKs), which are in turn activated by SEK kinases. The Ras-like small G proteins implicated in SEK kinase activation are Rac and Cdc-42. In this case, it appears that Rac/Cdc-42 triggers activation of SEK kinase by stimulating its phosphorylation by still another protein kinase termed p21-activated kinase (PAK). Thus, PAK can be considered a MAPK kinase kinase kinase, which is analogous to the cascade of protein kinases found in yeast (Fig. 23-4). 

Shi, C. S. and J. H. Kehel, Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubcl3-UevlA/TNF receptor-associated factor 2 (TRAF2). J Biol Chem, 2003, 278(17), 15429-34. 

An important subgroup of MAP kinases has the transcription factor c-Jun as substrate. These kinases are known as c-Jun NH2 terminal kinases (INK) or, due to their activation by stress signals, as stress activated protein kinases (SAPK). The JNK/SAPK proteins are part of their own protein kinase module that conducts stress signals further at the transcription level, and this signaling pathway is therefore known as the JNK/ SAPK pathway. 

C-Jun-N-terminal kinases The JNK/Stress-activated protein kinases (SAPKs) do not respond well to mitogens but are strongly activated by agents that induce cellular stress. These kinases phosphorylate C-Jun transcription factor. The sequence of the tripeptide motif for JNK is Thr-Pro-Tyr. The activators of cytokine and tyrosine kinase receptors transduce signal to the upstream MAPKKKs. These... 

Two very similar groups of kinases with apparent molecular masses in the 46-57 kDa and 38 kDa ranges, respectively, were soon discovered in experiments with stressful stimuli such as the application of protein biosynthesis inhibitors or exposure of cells to (unphysiological) ultraviolet (UV) radiation (UVC <280 nm) [38] or lipopolysaccharide [39,40]. These stress-activated protein kinases (SAPK) are also proline-directed kinases that are activated by dual phosphorylation. The phosphorylation motif, however, differs from that of the classical MAPK, and is Thr-Pro-Tyr and Thr-Gly-Tyr, respectively, in the two SAPK groups. 

Cd has been shown to be a specific inducer of c-fos in mesangial cells through activation of Erk kinase, protein kinase C and stress-activated protein kinase (SAPK) pathways [223, 224] and may therefore also play a carcinogenic role in the kidney. 

Abbreviations used tumor necrosis factor-a (TNF-a), interferon-y (INF-y), interleukin-ip (IL-1P), sphingosine kinase (SK), protein kinase C (PKC), sphingomyelinase (SMase), extra-cellular-regulated mitogen-activated protein kinase (ERK), stress-activated protein kinase (SAPK), ceramide activated protein kinase (CAPK), ceramide activated protein phosphatase (CAPP), mitogen activated kinase (MEK), phosphatidylinositol-3-kinase (PI3K), phospholipase C (PLC), phospholipase D (PLD), SIPR (SIP receptor). 

Fig. 13.2. TNFa receptor-signaling activates of all three members of the mitogen activated protein kinase (MARK) family, including the p44/p42 (also termed extracellular signal-related kinases, ERK-1/2), the c-Jun-NH2-terminal kinases (JNK also termed stress-activated protein kinases, SAPK), and p38 MARK (also termed stress/cytokine-activated kinases). U0126 blocks MARK kinase (MEK) phosphorylation of ERKl/2.

Active MAPKs function as modulators for differentiation, proliferation, cell death, and survival. Commonly, the activation of ERK 1/2 has been linked to cell survival, whereas INK and p38 [also called the stress-activated protein kinases (SAPKs)] have been associated with apoptosis [30]. This perspective is an oversimplification, and the actual roles are highly dependent on the cell type, the state of cell development, the kind of stimulus, and the context of stimulation. 

Seko Y, Takahashi N, Tobe K, Kadowaki T, Vazaki Y. Hypoxia and hypoxia/ reoxygenation activate p65PAK, p38 mitogen-activated protein kinase (MAPK), and stress-activated protein kinase (SAPK) in cultured rat cardiac myocytes. Biochem Biophys Res Commun 1997 239 840-844. 

Arnoczky, S. P, T. Tian, M. Lavagnino et al. 2002. Activation of stress-activated protein kinases (SAPK) in tendon cells following cychc strain The effects of strain frequency, strain magnitude, and cytosohc calcium. Journal of Orthopaedic Research 20(5) 947-952. 

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