Phosphorylation cascades protein kinases

Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues—and subsequent dephosphorylation by protein phosphatases—regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades which respond to hormonal or second messenger signals constimte a bio-organic computer that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response. 

Behar M, Hao N, Dohlman HG, Elston TC. Mathematical and computational analysis of adaptation via feedback inhibition in signal transduction pathways. Biophys. J. 2646 93 806-821. Markevich NI, Hoek JB, Kholodenko BN. Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J. CeU Biol. 2004 164 353-359. 

Figure 20-2. The mobilization of glycogen in the liver in response to hormonal signals. Binding of the hormones glucagon and/or epinephrine causes the activation of adenylate cyclase resulting in the production of cyclic AMP, which activates protein kinase A. By phosphorylation reactions, protein kinase A inactivates glycogen synthase, activates a cascade that results in active glycogen phosphorylase, and produces an active inhibitor of protein phosphatase 1.

When certain hormones bind to their receptors in adipose tissue, a cascade mechanism releases fatty acids and glycerol from triacylglycerol molecules. Triacylglycerol lipase (sometimes referred to as hormone-sensitive lipase) is activated when it is phosphorylated by protein kinase. Protein kinase is activated by cAMP. After their transport across the plasma membrane, fatty acids are transported in blood to other organs bound to serum albumen. 

When glycogen degradation is activated by the cAMP-stimulated phosphorylation cascade, glycogen synthesis is simultaneously inhibited. The enzyme glycogen synthase is also phosphorylated by protein kinase A, but this phosphorylation results in a less active form, glycogen synthase b. 

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. 

Tyrosine kinase activation can also initiate a phosphorylation and dephosphorylation cascade that involves the action of several other protein kinases and the counter-... 

The kinases themselves can be arranged into phosphorylation cascades so that one kinase phosphorylates another, which, in turn, phos-phorylates another. This often leads to some funny names, such as MAP kinase kinase kinase. This means a mitogen-activated protein kinase that phosphorylates MAP kinase kinase. The activated MAP kinase kinase then phosphorylates and activates MAP kinase. 

The PROTEIN KINASE CASCADE amplifies the original extracellular signal by increasing levels of cAMP, which activates cAMP-dependent protein kinase, which phosphorylates specific proteins. 

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... 

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). 

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... 

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