The MAP Kinase Cascade

The duration of signaling influences how a cell responds to a particular stimulus. For example, brief activation of the MAP kinase cascade in the neuronal cell line, PCI 2, results in proliferation, while sustained... 

Role of membrane attachments The Ras-stimulated cascade depends on the binding of components of the cascade to the cell membrane. Ras itself is attached to the plasma membrane and it activates Raf (the first enzyme in the MAP kinase cascade) by causing it to bind to the membrane. 

Phosphorylated IRS-1 activates a second signaling pathway by interacting with an 85-kDa SH2-containing protein that is a subunit of phophatidylinositol 3-kinase.384 386 This activates the 110-kDa catalytic subunit of the 3-kinase, which catalyzes formation of phosphatidylinositol 3-phosphate as well as Ptdlns (3,4)P2 and Ptdlns (3,4,5)P3.387/387a These compounds, which remain within membranes, activate other branches of the signaling cascade, some of which may converge with those of the MAP kinase cascade. However, there appears to be specific activation of a ribosomal Ser/Thr kinase that, among other activities, phosphorylates ribosomal protein S6, a component of the small ribosomal subunit.388 It also phosphorylates some isoforms of protein kinase C and other enzymes. Ptdlns 3-kinase may also activate 6-phosphofructo-2-kinase (Fig. 11-2, step ti).384/388... 

Opioid receptors. Direct binding of highly radioactive opiates has permitted localization of specific opiate receptors of several types.863-866 The three major types (p, 8, k) are all 7-helix receptors coupled to adenylate cyclase, K+ and Ca2+ channels, and the MAP kinase cascade.866 The p receptors bind morphine most tightly.867 8673 These receptors are found in various cortical and subcortical regions of the brain. Most narcotics are polycyclic in nature and share the grouping indicated in Fig. 30-30. However, the flexible molecule methadone binds to the same receptors.868 Among antagonists that block the euphoric effects of opiates the most effective is naloxone (Fig. 30-30). 

E. D., Muller, G., Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors, Nat. Biotech. 2002, 20 370-375. 

The delta opioid receptor is a member of the large family of seven trans-membrane-spanning G protein-coupled receptors (GPCRs), as discussed extensively in Chapter 2. Delta opioid receptors modulate many intracellular effectors through their activation of GTP-binding proteins (G proteins), including adenylyl cyclase, K+ channels, Ca2+ channels, the MAP kinase cascade, phospholipase C, and intracellular Ca2+ release [1] (see Chap. 5). 

Rg. 3.14 The chain of events by which a RTK activates Ras. A compiex is formed, containing the activated, phosphorylated RTK, and the linker, Grb2 (or She), which recrurts the exchange factor, Sos. Contacts are through SH2 and SH3 domains of the coupiing partners.i it is assumed that activation of Sos is due to its transiocation from the cytosol to the membrane where the receptor and Ras are looated.The activated, GTPTjound form of Ras is formed, which in turri activates the Raf kinase and the MAP kinase cascade. 

Fig. 4.1 Growth-factor signals are channelled in the Raf/Ras pathway, resulting in cellular proliferation and differentiation, whereas stress and cytokine signals are directed via MAPKKKs and MAPKKs to JNKs 1 and 2 and the p38 MAP kinase. They cause growth inhibition and apoptosis. Second messengers, such as lipid messengers, may also adress the MAP kinase cascade and elicit specific cellular responses. Included in the scheme are upstream kinases, such as Raf, that in turn activate the MAPKKs (not shown), and eventually the p44 MAPKs 1 and 2 (or ERKs). (This scheme is simple and not complete, because some kinases participating in these signalling pathways are not yet defined.)...

Fig. 4.3 Pouyssegur and colleagues found that in the resting dormant state of a cell (a) the MAP kinases are kept in the cytoplasm by interaction with the upstream cytosolic kinases of the MAP kinase cascade, (b) Activation of the MAP kinase cascade by a growth factor uncouples the MAPK from upstream MAPKKs and initiates translocation of MAPK to the nucleus, where it signals entry into the S phase of the cell cycle. In the nucleus, MAPK is retained by short-lived nuclear anchoring proteins. When their proteolytic removal is blocked, the residence time of MAPK in the nucleus is prolonged.

The response of cytosolic kinases to the input signal can be regulated by monomeric G proteins. An example is the control of the Raf-1 kinase in the MAP kinase cascade by the GTP/GDP on/off switch function of Ras. Signals passing through the Ras control point can be routed in different directions. The right of way is controlled by kinases. The specificity of the kinases overrules the coupling promiscuity of Ras, and other linkers. 

An essential requirement of all regulatory processes is reversibility. Prime examples are the on/off switch of a monomeric G protein, Ras, which controls signalling through the MAP kinase cascade and the reversal of phosphorylation by phosphatases, catalysing... 

Similar to the MAP kinase cascades for protein phosphorylation, protease cascades exist, in which downstream proteases are activated by the action of upstream proteases (3). One of the most famous cascades is the caspase cascade that leads to apoptosis (Fig. 22) (11, 136). Caspases are Cys proteases that cleave the amide bond specifically after an Asp residue. Two types of caspases exist, initiator caspases (Caspase 2, 8, 9, 10) and effector caspases (Caspase 3, 6, 7). Both initiator and effector... 

NISHIDA E, GOTOH Y. The MAP kinase cascade is essential fev diverse signal transduction pathways. Trends Biol Sd 10 128-131,1993. 

This chapter has emphasized the role of DNA mutations in the pathways leading to cancer. However, a number of chemicals are cancopromoting purely because of their ability to activate certain enzymes, where there exists no direct or indirect influence on DNA mutations. This functional class of compounds promotes or prevents cancer orJy when present on a chronic basis, i.e, at elevated levels every day for many years. The notion that bile salt metabolites may result in chronic stimulation of protein kinase C was discussed earlier. The related event of fiber decreasing exposure of the colon to bile salts was also outlined. The chronic exposure theory applies to the phorbol esters that are present in certain plants. People who drink tea made from the plant Croton flaveti tend to acquire esophageal cancer. This cancer results from chronic exposure to phorbol esters, which occurs in the leaf extract or in an oil prepared from the plant (croton oil). The phorbol esters enter the cell, bind to protein kinase C, and activate this enzyme. Activated protein kinase C, in turn, activates the MAP kinase cascade (Ueda et aL, 1996). The continual activation of protein kinase C, when combined with mutations in specific proto-oncogenes, may lead to cancer and sustain the cells in the cancerous state. 

Avruch, J., et al. 2001. Ras activation of the Raf kinase tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog. Harm. Res. 56 127-155. 

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