External signal-regulated protein kinase

ERK, external signal-regulated protein kinase (MAPK)... 

A protein kinase or protein phosphatase may be regulated by different signal transduction pathways. Thus, different external stimuli may influence the phosphorylation status of a protein. This differential stimulation may be mediated by the subunits of the enzyme, for example. For phosphorylase kinase, a Ca signal is registered by the Ca T calmodulin subunit whereas a cAMP protein kinase A signal is picked up in the form of a phosphorylation of the a and P subunits. Which of the signals comes into play depends on the current metabolic situation. 

The two-component pathway is characterized by two functional elements. A histidine-specific protein kinase functions as a sensor that registers an external signal and passes this on to a downstream response regulator. The latter is activated by phosphorylation during the process of signal transduction, triggering other reactions in the cell (Fig. 12.3). 

The composition of the two-component pathway is very variable. The nature of the external signal and the reactions triggered in the cell may be very diverse. The sensor kinase may be a part of the receptor that registers the signal, or it may be on a polypeptide chain separate from the receptor. Furthermore, there are different mechanisms of coupling of the main functions of the two-component pathway. The sensor and reaction regulator may be on a single polypeptide or they may be on separate proteins. In addition, the proteins involved may be membrane proteins. 

The control of cellular proliferation and differentiation in response to external stimuli is achieved by signal transduction pathways, which are regulated in part by the co-ordinated action of protein kinases and phosphatases. In eukaryotic cells the protein kinases involved fall primarily into two classes, those that phosphorylate tyrosine residues and those that are specific for serine and threonine residues. Prokaryotic cells also rely on protein phosphorylation cascades for regulation of cellular activities, but the kinases involved are primarily histidine kinases, which are part of the sensing domain of two-component regulatory systems. These histidine kinases and their associated response regulators are involved in a range of adaptive responses by bacteria. 

To illustrate how the active site binds a specific substrate and then promotes a chemical change in the bound substrate, we examine the action of cyclic AMP-dependent protein kinase, now generally referred to as protein kinase A (PKA). This enzyme and other protein kinases, which add a phosphate group to serine, threonine, or tyrosine residues in proteins, are critical for regulating the activity of many cellular proteins, often in response to external signals. Because the eukaryotic protein kinases belong to a common superfam-lly, the structure of the active site and mechanism of phosphorylation are very similar in all of them. Thus protein kinase A can serve as a general model for this important class of enzymes. 

---