Mitogen-activated protein kinase map

Mitogen activated protein kinase. MAP Kinase Cascade... 

Activation of Mi, M3, and M5 mAChRs does not only lead to the generation of IP3 followed by the mobilization of intracellular Ca2+, but also results in the stimulation of phospholipase A2, phospholipase D, and various tyrosine kinases. Similarly, M2 and M4 receptor activation does not only mediate the inhibition of adenylyl cyclase, but also induces other biochemical responses including augmentation of phospholipase A2 activity. Moreover, the stimulation of different mAChR subtypes is also linked to the activation of different classes of mitogen-activated protein kinases (MAP kinases), resulting in specific effects on gene expression and cell growth or differentiation. 

The biochemical mechanism of Mos action is not yet established. Mos has been found to phosphorylate cyclin B in vitro, and it is possible that this phosphorylation directly inhibits cyclin B proteolysis (Roy et al., 1990). However, such a direct effect of phosphorylation on cyclin B stability remains to be demonstrated, and it is alternatively possible that Mos inhibits (directly or indirectly) the proteolytic pathway responsible for cyclin B degradation. Mos has recently been found to stimulate mitogen-activated protein kinase (MAP kinase) in Xenopus oocytes,... 

The mitogen-activated protein kinase cascade is second-messenger-independent. Although the second-messenger-dependent protein kinases were identified first as playing an important role in neuronal function, we now know that many other types of protein serine-threonine kinase are also essential (Table 23-1). Indeed, one of the most critical discoveries of the 1990s was the delineation of the mitogen-activated protein kinase (MAP kinase or MAPK) cascades. 

Figure 10.6 Schematic representation of the mitogen-activated protein kinase (MAP) cascades in mammalian cells. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

PAF activates mitogen activated protein kinase (MAP Kinase) in platelets. PAF stimulated P42 MAP Kinase lAPK) in sheep platelets and to a lesser extent P44 MAPK. S6 kinases were also stimulated by PAF (Sa ei et. al., 1993). It is likely that PKC is involved in fiiis process. However, any precise role for platelet MAPK in PAF responses awaits future investigation. 

Consistent with the sequence similarities between the ORLl and opioid receptors, activation of the ORLl receptor triggers the same signal transduction mechanisms as used by the opioid receptors. Thus activation of ORLl receptors inhibits both forskolin-stimulated adenylyl (yclase and currents and activates several other effectors, including inward rectifying channels, protein kinase C, mitogen-activated protein kinase (MAP kinase) and phospholipase C (see Ref 89 for a review). 

FIGURE 10.6 Schematic representation of the mitogen-activated protein kinase (MAP) cascades in mammalian cells. 

It was originally recognised by Dabrowska et al. (1978) that calmodulin was part of the active holoenzyme MLCK complex. The association of calmodulin with MLCK is rapid and appears to be diffusion limited. It could be described by a two-step process, a bimolecular step and an isomerisation (Torok and Trentham 1994). The time required for activating MLCK by Ca +/calmodulin may contribute to the latency of about 400-500 ms at 37 C which precedes increases in LC20 phosphorylation (Miller-Hance et al. 1988). The interaction of Ca Vcalmodulin with MLCK may be modulated by phosphorylation of MLCK. Purified MLCK is a substrate for protein kinase A (Conti and Adelstein 1981), the multifunctional Ca /calmodulin dependent protein kinase II (Hashimoto and Soderling 1990, Ikebe and Reardon 1990), protein kinase C (PKC) (Nishikawa et al. 1983) and mitogen activated protein kinase (MAP kinase, Klemke et al. 1997). Phosphorylation of MLCK by these protein kinases may alter the Ca -sensitivity of the enzyme and hence of contraction, as will be discussed below. 

Mitogen-activated protein kinase (MAP kinase) is another kinase that is activated upon stimulation with agonists or depolarization with high K+ (Adam et al. 1995 Katoch and Moreland, 1995 Gerthoffer et al. 1997). 

Further evidence for the importance of imine formation for T cell function was derived from the discovery that tucaresol and other small molecules with an aromatic aldehyde moiety capable of forming Schiff bases, produces a signal to CD4+ T helper (Th) cells [62]. Tucaresol reacts in vitro with free CD4+ T cell surface amines from receptors like CD2 within seconds to cause a co-stimulatory signal to produce a Thl response with the release of interferon y (IFN-y) and a 5- to 10-fold increase of interleukin 2 (IL-2). Such a Thl response is believed to be important for intracellular pathogens such as viruses, mycobacteria, protozoa and tumors. Studies in vivo show that low concentrations of tucaresol enhance not only CD4+ Th cells in response to antigens but also CD 8+ CTL and that this response has a beneficial effect in antiviral and antitumor therapy in animal models. Mechanistically, formation of Schiff bases with tucaresol has been shown to greatly affect intracellular potassium and sodium ion concentrations by the co-stimulation of mitogen-activated protein kinase (MAP kinase) and thus activation of ion channels in T cells [62,102]. Some of these mechanistic features are depicted in Fig. 19. 

Activation of Ras initiates a complicated protein kinase cascade that culminates in the activation of a mitogen-activated protein kinase (MAP kinase). At its core are three protein kinases. The first, Raf, is activated by binding to Ras. Raf, which is functionally a MAP kinase kinase kinase, phosphorylates serine and threonine residues on the second kinase (known as MEK in mammals), leading to its activation. Frmctionally, MEK is a MAP kinase kinase. Finally, activated MEK phosphorylates specific serine and tyrosine residues on a MAP kinase (called Erk in mammals), which is then able to phosphorylate its downstream targets. 

In vitro, purified group IV PLA2 is a substrate for at least three major protein kinases protein kinase C (PKC), cyclic AMP-de-pendent protein kinase (PKA) and mitogen-activated protein kinase (MAP kinase). MAP kinase phosphorylates group IV PLA2on a serine residue (serine 505), causing a dramatic increase in the enzyme s catalytic activity the sites phosphorylated by PKC or PKA are different from the MAP kinase site and these phosphorylations... 

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