ABSTRACT
Cellular homeostasis is maintained through a series of complex biochemical pro cesses that are tightly controlled both spatially and temporally. Perturbation of any one or more of these biochemical processes conceivably can lead to the failure of this homeostasis, with deleterious consequences to the cells, the tissue of which the affected cells are a part, and finally the organism comprising the affected tissues. Such perturbations are recognized in many disease states such as cancer. In some instances exposure to exogenous agents such as toxic environmental chemicals, natural tox ins, or UV light may perturb cellular homeostasis through disruption of regulatory components that are involved in this process. This is considered a toxic response that leads to failure of a specific organ function. It is important, therefore, to understand the complex biochemical processes taking part in cell growth and proliferation and how foreign chemicals interfere with these biochemical pathways and elicit a toxic response. This chapter limits its discussion to these biochemical pathways regulated
by protein kinases, enzymes that phosphorylate cellular proteins by transferring the phosphate group from ATP to target proteins of the cell to alter their function. It long has been recognized that kinase phosphorylation of cellular proteins plays a major role in cell growth and proliferation and in the function of hormones and growth factors (1-5). In many cases, phosphorylation activates the function of a protein; however, there are a few examples in which phosphorylation inactivates a protein so as to release an associated factor that produces the response. The known protein kinases can be grouped broadly into two major classes: the tyrosine kinases and serine/threonine kinases. The former class of kinases phosphorylates proteins at tyrosine amino-acid residues and the latter at serine/threonine residues. There are some ex ceptions to this classification that are discussed later in this chapter. The substrate proteins, however, may be phosphorylated by either of these two kinase types at the appropriate residue. Although phosphorylation of proteins is a covalent modifica tion, the process is reversible; that is, phosphorylated proteins are dephosphorylated by enzymes termed protein phosphatases. Protein phosphorylation by kinases and dephosphorylation by phosphatases play a central role in many cellular processes and in the transmission of extracellular signals to the interior of the cell for growth control. Perturbations in the regulatory mechanisms of protein kinases have been known to be caused by synthetic and natural chemicals. Such a modification by ex ogenous chemicals may lead to loss of growth control, such as that which occurs during carcinogenesis.
