MAPK cascades

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... 

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. 

Activation of PI-PLC-linked receptors, such as the mAChR, results in increased PKC activity. Since the addition of phorbol esters, which are PKC agonists (see Ch. 20), results in phosphorylation of Raf, this mechanism may provide an explanation for the ability of PI-PLC-coupled receptors to activate MAPK. A recently discovered protein tyrosine kinase PYK2, which is enriched in the CNS, is also activated by PKC. Like PTK-X, PYK2 phosphorylates SHC and recruits the Grb2-SOS complex, which results in activation of the MAPK cascade. PYK2 is also activated by... 

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. 

The basic scheme for MAPK cascades is shown in Figure 23-4. MAPK is part of a phosphorelay system composed of three sequentially activated kinases [13]. MAPK, inactive under basal conditions, is activated by phosphorylation by another protein kinase, termed... 

Several key questions remain with regard to the regulation of tyrosine hydroxylase by phosphorylation. What is the precise effect of the phosphorylation of each of these serine residues on the catalytic activity of the enzyme How does the phosphorylation of multiple residues affect enzyme activity Does the phosphorylation of one residue affect the ability of the others to be phosphorylated Tyrosine hydroxylase provides a striking example as to how multiple intracellular messengers and protein kinases converge functionally through the phosphorylation of a single substrate protein. Phosphorylation of tyrosine hydroxylase by cAMP-dependent and Ca2+-dependent protein kinases and by MAPK cascades... 

CREB is also phosphorylated on serine 133 by stimulation of growth factor signaling cascades [63]. This occurs via a complex pathway involving MAPK cascades (Fig. 23-9). Thus, as outlined earlier, nerve growth factor and related neurotrophins that act on receptor tyrosine kinases lead to the successive activation of Ras, Raf, MEK and ERK. Activated ERK then phosphorylates and activates a serine-threonine kinase, RSK, particular subtypes of which directly activate CREB via the phosphorylation of serine 133. 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

Another major way by which intracellular messenger pathways interact is via phosphorylation of the same substrate proteins. There are numerous examples of this, some discussed earlier in this chapter. One striking example is provided by CREB, which is phosphorylated on the same single serine residue by PKA, CaMK and RSK, activated by the MAPK cascade. 

As mentioned above, activation of TrkA by NGF may result in cellular proliferation, differentiation or survival. Exactly how different TrkA-induced signal transduction mechanisms are translated into each one of these functions is incompletely understood. It has been suggested that proliferation and differentiation are mediated by activation of the MAPK cascade while survival is mediated by activation of PI-3-K. The competing actions of neurotrophins on... 

Zhou, X., Lu, X., Richard, C., Xiong, W., Litchfield, D.W., Bittman, R., and Arthur, G., 1996, l-O-octadecyl-2-O-methyl-glycerophosphochohne inhibits the transduchon of growth signals via the MAPK. cascade in cultured MCF-7 ceUs. J. Clin. Invest. 98 937-944... 

Bogoyevitch MA, Boehm I, Oakley A, et al. Targeting the JNK MAPK cascade for inhibition basic science and therapeutic potential. 

First, it provides another mechanism of desensitization, in that receptors at the cell surface produce an increase in cAMP via G whereas internalized receptors produce a decrease in cAMP levels via G,. Second, it has been found that Py subunits released from activated G, are capable of stimulating the MAPK cascade. Thus, at least for the P2 receptor, internalization functions not only to temporarily desensitize the receptor to activation of the cAMP pathway but also to initiate signaling to MAPK. Recently, a number of other G protein-coupled receptors have been found to signal to the MAPK pathway via G as well as G and G and many of these receptors seem to require internalization for such signaling to take place. 

Activation of TGPp is accompanied by multiple phosphorylation on cytoplasmic parts of the receptor this includes Tyr phosphorylation in addition to Ser/Thr phosphorylation. It is assumed that these autophosphorylations occur in trans, i.e., between the protomers of the receptor. Prom the activated TGPp receptor, signals are directed to the transcription level. A set of proteins, known as Smad proteins, are involved in this signal conduction (see Pig. 12 review Heldin et al., 1997, Massague, 1998). Besides Smad proteins, G-proteins and the MAPK cascade are also involved in the downstream signaling of TGPp family members. 

FIGURE 12-18 /3-Arrestin uncouples the serpentine receptor from its G protein and brings together the three enzymes of the MAPK cascade. The effect is that one stimulus triggers two distinct response pathways the path activated by the G protein and the MAPK cascade. 

---