Protein phosphorylation–dephosphorylation is a highly versa tile and selective process. Not all proteins are subject to phosphorylation, and of the many hydroxyl groups on a protein’s surface, only one or a small subset are targeted. While phosphorylation of some enzymes increases their catalytic activity, the phosphorylated form of other enzymes may be catalytically inactive (Table 1). Alternatively, phosphorylation may affect a protein’s location within the cell, susceptibility to proteolytic degradation, responsiveness to regulation by allosteric ligands, or responsive ness to covalent modification on some other site.

Table1. Examples of Mammalian Enzymes Whose Catalytic Activity Is Altered by Covalent Phosphorylation–Dephosphorylation

Many proteins can be phosphorylated at multiple sites. Others are subject to regulation both by phosphorylation dephosphorylation and by the binding of allosteric ligands, or by phosphorylation–dephosphorylation and another covalent modification. If the protein kinase that phosphorylates a particular protein responds to a signal different from that which modulates the protein phosphatase that catalyzes dephosphorylation of the resulting phosphoprotein, then even the simplest phosphoprotein becomes a decision node. Its functional output reflects the phosphoprotein’s degree or state of phosphorylation, which reflects the relative strength of the signals that modulate the protein kinase and protein phosphatase. If the phosphorylation (or dephosphorylation) of a given site can be catalyzed by more than one protein kinase (or protein phosphatase), the phosphoprotein can then integrate and process several input signals.

The ability of many protein kinases to phosphorylate multiple proteins enables coordinate regulation of cellular activities. For example, 3-hydroxy-3-methylglutaryl-CoA reductase and acetyl-CoA carboxylase—the rate-controlling enzymes for cholesterol and fatty acid biosynthesis, respectively—both can be inactivated through phosphorylation by the AMP activated protein kinase. When this protein kinase is activated either through phosphorylation by yet another protein kinase or in response to the binding of its allosteric activator 5′-AMP, the two major pathways responsible for the synthesis of lipids from acetyl-CoA are both inhibited.

The interplay between protein kinases and protein phosphatases, between the functional consequences of phosphorylation at different sites, between phosphorylation sites and allosteric sites, or between phosphorylation sites and other sites of covalent modification provides the basis for regulatory networks that integrate multiple inputs to evoke an appropriate coordinated cellular response. In these sophisticated regulatory networks, individual enzymes respond to different internal and environmental signals.