MAPK-kinase cascade

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

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

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. 

A second family of MAPKs is referred to as stress-activated protein kinases (SAPKs) [3,14,15]. This includes JNKs, or Jun kinases, named originally for their phosphorylation of the transcription factor c-Jun. SAPKs were first identified in peripheral tissues on the basis of their activation in response to cellular forms of stress, which include X-ray irradiation and osmotic stress. More recently, they have been demonstrated to be activated in brain by several cytokines as well as by synaptic activity [16]. As shown in Figure 23-3, SAPKs are activated by SAPK kinases (SEKs), which are in turn activated by SEK kinases. The Ras-like small G proteins implicated in SEK kinase activation are Rac and Cdc-42. In this case, it appears that Rac/Cdc-42 triggers activation of SEK kinase by stimulating its phosphorylation by still another protein kinase termed p21-activated kinase (PAK). Thus, PAK can be considered a MAPK kinase kinase kinase, which is analogous to the cascade of protein kinases found in yeast (Fig. 23-4). 

Sweat J (2001) The nem-onal MAP kinase cascade a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76 1-10 Szapiro G, Vianna MRM, McGaugh JL, Medina JH, Izquierdo 1 (2003) The role of NMDA glutamate receptors, PKA, MAPK, and CAMKll in the hippocampus in extinction of conditioned fear. Hippocampus 13 53-58... 

Figure 11-13 (A) A simplified version of the mitogen-activated kinase (MAPK) signaling cascade. At left is shown a hormone receptor, e.g., that for the epidermal growth factor (EGF). The receptor tyrosine kinase undergoes autophosphorylation on numerous tyrosines. The resulting phosphotyrosyl (Y-P) groups bind to SH2 domains of adapters such as Grb2 and She.

How elicitors affect JA biosynthesis and how the JA signal is transduced to affect gene expression is largely unknown. Several reports have implicated the activation of a wound-responsive MAPK cascade upstream of JA biosynthesis [61-63]. Downstream of the ODA pathway there are also one or more protein kinases involved in transduction of the JA signal [64]. A protein kinase (cascade) ultimately changes the activity of transcription factors, which regulate the... 

Whereas, activation of MAPKKs and MAPKs (also known as extracellular signal-responsive kinases, ERKs), through traw -phosphorylation reactions is fairly well understood, activation of the upstream MAPKKKs, such as the Raf family of protein kinases, is more complicated. There are at least three human Raf kinases Raf-1, Raf-A, and Raf-B. The activation of the Raf kinase is controlled by Ras. This is a central point of control of the whole 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.

MAPKs are a family of well-conserved serine/threonine kinases that have a central role in a wide variety of protein kinase cascades. These cascades consist of three kinases, a mitogen activated protein kinase (MAPK), a MAPK kinase (MAPKK) and a MAPK kinase kinase (MAPKKK), which modulate each other in a chain reaction. In other words, MAPKKK activates MAPKK which in turn activates MAPK. 

The human genome encodes over 2000 protein kinases that are finely turned off and on by different signals. For instance, the MAPK are activated through complex but controlled kinase cascades in response to a number of factors, including stress and cytokines. Experimental protein kinase activation can be performed by exogenous agents of plant or marine origin such as phorbols or bryostatins, respectively. 

---