MAPK

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]. 

Several patients have exhibited a clinical picture resembling FHH, but no CaR mutations could be identified. These individuals also exhibited various forms of autoimmunity (e.g., antithyroid antibodies) and harbored anti-CaR antibodies that reduced the high CaQ+ -evoked stimulation of MAPK and PLC in cells transfected with the wild type receptor. Thus both antireceptor antibodies and mutations in the CaR can render the receptor resistant to activation by Caq+, producing a clinical picture of mild, PTH-dependent hypocalciuric hypercalcemia [3]. 

Some patients with reduced or absent parathyroid function, e.g., primary hypoparathyroidism, harbor anti-CaR antibodies (Fig. 2) [4]. In two patients, the antibodies were shown to activate the CaR as assessed by stimulation of MAPK and PLC. Tims, analogous to activating mutations of the CaR, anti-CaR antibodies can increase the sensitivity of the receptor to CaQ+, thereby resetting parathyroid and kidney to maintain hypocalcemia. 

Mitogen activated protein kinase (MARK) cascades are three kinase modules activated by phosphorylation. The three kinase modules are composed of a MAPK, a MAPKK, and a MAPKKK. There are multiple members of each component of the MAPK cascade that are conserved from yeast to human. Activation of selective MAPK modules by specific stimuli regulates cell functions such as gene expression, adhesion, migration, differ entiation, and apoptosis. 

MAPK cascades are composed of three cytoplasmic kinases, the MAPKKK, MAPKK, and MAPK, that are regulated by phosphorylation (Fig. 1) [1, 2]. The MAPKKK, also called MEKK for MEK kinase, is a serine/threonine kinase. Selective activation of MAPKKKs by upstream cellular stimuli results in the phosphorylation of MAPKK, also called MEK for MAP/ERK kinase by the MAPKKK. MAPKKK members are structurally diverse and are differentially regulated by specific upstream stimuli. The MAPKK is phosphorylated by the MAPKKK on two specific serine/ threonine residues in its activation loop. The MAPKK family members are dual specificity kinases capable of phosphorylating critical threonine and tyrosine residues in the activation loop of the MAPKs. MAPKKs have the fewest members in the MAPK signaling module. MAPKs are a family of serine/threonine kinases that upon activation by their respective MAPKKs, are capable of phosphorylating cytoplasmic substrates as well as... 

MAP Kinase Cascades. Figure 1 Organization of MAPK cascades. See text for details. 

MAP Kinase Cascades. Table 1 Pharmacological Inhibitors of MAPK Cascades... 

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

English JM, Cobb MH (2002) Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 23 40—45... 

Increase in inositol phosphates and cytosolic [Ca2+] Activation of MAPK pathway NN SR 142948A ... 

Human Stably transfected CHO cells Increase in inositol phosphates, cytosolic [Ca2+], arachidonic acid activation of MAPK pathway SR 48692 NT ... 

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