MAPK kinase

E. G protein-conpled receptors /3-Adrenergic receptor kinase (BARK) Rhodopsin kinase II. Ser/Thr/Tyr protein kinases MAP kinase kinase (MAPK kinase) —TEY— phosphorylation by... 

The anthrax toxin is a tripartite toxin and consists ofthe binding component protective antigen (PA), the lethal factor (LF), which is a metalloprotease, and the edema factor (EF), which is a calmodulin-dependent adenylyl-cyclase. Both enzyme components are translocated via PA into target cells. PA is activated by furin-induced cleavage and forms heptamers, which are similar to the binding components of C2 toxin and iota toxin. In the low pH compartment of endosomes, the heptamers form pores to allow translocation of LF and EF. LF cleaves six of the seven MEKs (MAPK-kinases) thereby inhibiting these enzymes. The functional consequence is the blockade of the MAPK pathways that control cell proliferation, differentiation, inflammation, stress response, and survival. Whether this is the reason for the LT-induced cell death of macrophages is not clear [1]. 

This intermediate MAPK activator (MAPK kinase, MAPKK) is a 45 kDa phosphoprotein capable of phosphorylating MAPK on serine/threonine and tyrosine residues (Matsuda et al., 1992 Nakielny et al., 1992a Kosako et al., 1993). Like MAPK, the activity of MAPKK is regulated by phosphorylation. During oocyte maturation MAPKK is phosphorylated on threonine residues (Kosako et al., 1992), and this phosphorylation is required for its activity (Ahn et al., 1991 Gomez and Cohen, 1991 Kosako et al., 1992 Matsuda et al., 1992). MPF can activate both MAPKK and MAPK in vitro, with the activation of MAPK lagging behind that of MAPKK however, MPF cannot activate either purified MAPKK or MAPK that has been dephosphorylated by phosphatases (Matsuda et al., 1992). MAPKK and MAPK are therefore believed to function downstream of MPF (Fig. 3). 

MAPK kinase (MAPKK). MAPK kinase itself is activated by phosphorylation by still another protein kinase, termed MAPK kinase kinase (MAPKKK). MAPK kinase kinase is activated upon interaction with a member of the Ras superfamily of small G proteins, which are bound to the plasma membrane (see Ch. 19). The exact mechanism of activation remains unknown, but it is believed that Ras and related proteins, in the activated GTP-bound form, can bind MAPK kinase kinase and thereby draw the kinase to the plasmalemma, where it is activated by as yet unknown factors, perhaps even an additional kinase, MAPK kinase kinase kinase (MAPKKKK). The mechanism governing the activation of Ras and related proteins by extracellular signals is quite complex and involves numerous Tinker proteins, for example She, Grb and Sos, that couple Ras to a variety of plasmalemma-associated growth factor-protein tyrosine kinase receptors (see Chs 20,24 and 27). 

The best characterized family of MAPKs in the brain are the extracellular signal-regulated protein kinases (ERKs) that are activated by the neurotrophins and related growth factors (Fig. 23-4) [14,15]. The MAPK kinases responsible... 

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). 

Mitogen-activated protein kinase phosphatases are dual-function protein phosphatases. Just as the MAPK kinases (e.g. MEKs) are unique as dual-functioning kinases in that they phosphorylate MAPKs on threonine and tyrosine residues, there are unique dual-function ing protein phosphatases that reverse the phosphorylation and activation of MAPKs [43], Such MAPK phosphatases (MKPs) were first identified as a product of vaccinia virus (VH1) and later found in all eukaryotic cells. There are now numerous members of this VH1 family of dual-functioning protein phosphatases. 

Fig. 10.2. Components and activation of the ERK pathway. Ordering and specificity of protein kinases in the ERK pathway. ExtraceUular signals are registered via receptor tyrosine kinases and passed on to the Ras protein. Ras GTP activates protein kinases belonging to the group of MAPKK kinases (Raf kinases and MEEKs). The MAPKK kinases phosphorylate the downstream group of protein kinases, the MAPKKs at two Ser residues. The MAPKKs phosphorylate the MAPKs (ERKl and ERK2) at a Tyr and a Thr residue, and thus are classified as dual specificity kinases. MAPK mitogenic activated protein kinase ERK extracellularly regulated kinase MEK MAP/ERK kinase MAPKK MAPK kinase MAPKKK MAPKK kinase MEKK MEK kinase.

Buemi et al. reported that the addition of Hey to the medium of smooth muscle cells in tissue culture caused a significant increase in cell proliferation and death through apoptosis and necrosis. When folic acid was added to the culture medium, homocysteine concentrations in media were reduced and the effects of Hey on the proliferation/apopto-sis/necrosis balance of cells in culture were inhibited (62). Ozer et al. (63) showed that the MAPK kinase pathway is involved in DNA synthesis and proliferation of vascular smooth muscle induced by homocysteine. 

Kartal Ozer N, Taha S, Azzi A. Homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells by interfering with MAPK kinase pathway. Biofactors 2005 24(1-4) 193-199. 

TAK-1 Transforming growth factor P-activated kinase is a MAPK kinase kinase... 

Chopra AP, Boone S, Liang X et al (2003) Anthrax lethal factor proteolysis and inactivation of MAPK kinase. J Biol Chem 278 9402-9406... 

Cedersund, G., Andersson, J., Roll, J., Knudsen, C., Danielsson, A., Str lfors, P., A core-box model for insulin signalling to MAPK-kinase response in human fat cells (in preparation). 

If we concentrate on one particular component of this map - the phosphorylation of PI(4,5)P2 to PI(3,4,5)P3 by PI3K and the dephosphorylation of PI(3,4,5)P3 to PI(4,5)P2 by F TEN, we can study the detailed enzyme kinetic scheme of this so-called phosphorylation-dephosphorylation cycle, which is illustrated in Figure 5.2. This illustrated cycle represents a ubiquitous module in biochemical signaling, ft could, for example, represent the phosphorylation of mitogen-activation protein kinase (MAPK) by MAPK kinase (MAPKK) and dephosphorylation of MAPK by MAPK phosphatase (MKP). 

MAPKK, MAPK kinase, mitogen activated protein kinase kinase... 

MAPKKK, MAPK kinase kinase, mitogen activated protein kinase kinase kinase MARGKS, myristoylated alanine-rich C kinase substrate... 

Johnson GL, Dohlman HG, Graves LM. MAPK kinase kinases (MKKKs) as a target class for small-molecule inhibition to modulate signaUng networks and gene expression. Curr. Opin. Chem. Biol. 2005 9 325-331. 

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