Activation of virtually all cell-surface receptors leads directly or indirectly to changes in protein phosphorylation through the activation of protein kinases, enzymes that add phosphate groups to specific residues of target proteins. Some receptors activate protein phosphatases, which remove phosphate groups from specific residues on target proteins. Phosphatases act in concert with kinases to switch the function of various target proteins on or off (Figure 15-3).

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The human genome encodes about 600 protein kinases and 100 different phosphatases. In general, each protein kinase phosphorylates specific amino acid residues in a specific set of target, or substrate, proteins whose patterns of expression generally differ in different cell types. Animal cells contain two types of protein kinases: those that add phosphate to the hydroxyl group on tyrosine residues (protein tyrosine kinases) and those that add phosphate to the hydroxyl group on serine or threonine (or both) residues (protein serine/threonine kinases). We will see in this chapter and the next that the catalytic subunits of all known protein kinases have similar three-dimensional structures, including an N-terminal and a C-terminal lobe; highly conserved amino acids cluster around the catalytic site and are essential for binding ATP. All kinases recognize their specific substrates by binding not only to the side chain to be phosphorylated, but also to specific amino acids that surround the phosphorylated residue. Thus one can analyze the amino acid sequences surrounding tyrosine, serine, and threonine residues in a protein and make a good prediction as to which kinases might phosphorylate those residues.

Many proteins are substrates for multiple kinases, each of which usually phosphorylates different amino acids in the protein. Each phosphorylation event has the potential to modify the activity of a particular target protein in different ways, some activating its function, others inhibiting it. An example we will encounter later is glycogen phosphorylase kinase, a key regulatory enzyme in glucose metabolism (see Figure 15-29). In many cases, addition of a phosphate group to an amino acid creates a binding surface that allows a second protein to bind; in the following chapter, we will encounter many examples of such kinase-driven assembly of multiprotein complexes.

Commonly the catalytic activity of a protein kinase itself is modulated by phosphorylation by other kinases, by the binding of other proteins to it, and by changes in the concentrations of various small intracellular signaling molecules and metabolites. Importantly, the activity of all protein kinases is opposed by the activity of protein phosphatases, some of which themselves are regulated by extracellular signals. Thus the activity of a protein in a cell can be a complex function of the activities of the usually multiple kinases and phosphatases that act on it. Several examples of this phenomenon that occur in regulation of the cell cycle are described in Chapter 19.