MAPK pathway

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]. 

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 ... 

FIG. 2. Pathway of CSF activation. The figure denotes p90Rsk as the target of the MAPK pathway required for generation of CSF activity, which inhibits the metaphase to anaphase transition in MIL... 

Subsequent experiments addressed the possibility that the target of MAPK responsible for these effects is p90Rsk. Upon injection of the constitutively active form of Rsk described above, oocytes undergoing the MI/MII transition in the presence of U126 remained in M phase with an elevated cyclin B level, a shift in Cdc27 and metaphase-arrested spindles. These results indicate that these actions of the MAPK pathway on the APC, like those involved in CSF arrest at metaphase, are mediated solely by p90Rsk. 

Mailer The bulk of the evidence is against a role for cyclin E/Cdk2. Whatever the additional component made during meiosis II is must persist into the embryo, because when the MAPK pathway on its own is put into the embryo, the arrest occurs, but when it is put into meiosis I, the arrest doesn t occur. 

The existence of nitric oxide synthase (NOS) in phagocytes (see below) provides a different kind of stimulation and the inhibition of NADPH oxidase. It has been found [72] that the low physiological concentrations of peroxynitrite formed from NO and superoxide stimulated superoxide production by PMA-activated human PMNs through the ERK MAPK pathway, while higher peroxynitrite concentrations inhibited it. Moreover, NADPH oxidase was inhibited by lidocaine, a sodium-blocker, in OZ-activated neutrophils through the suppression of p47phox translocation [73]. 

A further consideration is that receptors which primarily activate one pathway may, on occasion, activate a second pathway (Fig. 10-10). An example is the ability of GPCRs, such as a2-adrenergic receptors or mAChRs, to activate the MAPK cascade. Activation of adenylyl cyclase-linked receptors results in the release of G protein Py subunits, which, probably via an intermediary protein tyrosine kinase (PTK-X), stimulates phosphorylation of the adaptor protein SHC [36]. This in turn recruits the Grb2-SOS complex and activates the MAPK pathway. 

Ca2+, raising the possibility that the activity of ligandgated ion channels can also modulate the MAPK pathway. However, to date, there is no evidence to suggest that this regulation is reciprocal, that is, that activation of the MAPK pathway can modulate the activity of either GPCRs or ligand-gated ion channels. 

At present it is not known if all H3 receptor isoforms similarly activate the wide array of signaling pathways. In transfected cells, the rat H3(413) and H3(397) isoforms both inhibit adenylate cyclase more efficiently than does the hill length rat H3 receptor isoform (445 amino acids), but the former are less efficient in activating the MAPK pathway. Much less information is available for the human H3 receptor isoforms but shorter isoforms seem to couple more efficiently to G -proteins to inhibit cAMP production in transfected cells [40],... 

FIGURE 2 0-5 Activation of PLC-e by heterotrimeric (Gal2/i3, GI(Vy, GJ and small G protein (Ras, Rho and Rap) signaling pathways (see text for details). (Modified with permission from reference [11].) Note that Ras, activated via the mitogen-activated protein kinase (MAPK) pathway, may also activate PLCe. For details of the MAPK pathways and abbreviations, see Chapter 24. 

Cellular signals converge at the level of protein phosphorylation pathways. Individual intracellular messenger pathways, such as cAMP, Ca2+ and MAPK pathways, are often drawn as distinct biochemical cascades that operate in parallel in the control of cell function. While this is useful for didactic purposes, it is now well established that these various pathways function as complex webs, with virtually every conceivable type of interaction seen among them. 

Recruitment of Grb2 to the membrane activates the MAPK pathway. Grb2 is an adaptor molecule carrying one SH2 and two SH3 domains (Fig. 24-4). The Grb2 SH2 domain recognizes the tyrosine-phosphorylated moiety on certain RPTKs, such as EGFR (Fig. 24-8), and anchors... 

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