Glycogen Synthase Kinase 3 Mediates the Actions of Insulin

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As we saw in Chapter 12, one way in which insulin triggers intracellular changes is by activating a protein ki-nase (protein kinase B, or PKB) that in turn phosphor-ylates and inactivates GSK3 (Fig. 15-29; see also Fig. 12-8). Phosphorylation of a Ser residue near the amino terminus of GSK3 converts that region of the protein to a pseudosubstrate, which folds into the site at which the priming phosphorylated Ser residue normally binds (Fig. 15-28b). This prevents GSK3 from binding the priming site of a real substrate, thereby inactivating the enzyme and tipping the balance in favor of dephosphor-ylation of glycogen synthase by PP1. Glycogen phosphorylase can also affect the phosphorylation of glycogen synthase: active glycogen phosphorylase directly inhibits PP1, preventing it from activating glycogen syn-thase (Fig. 15-27).

Although first discovered in its role in glycogen metabolism (hence the name glycogen synthase kinase), GSK3 clearly has a much broader role than the regulation of glycogen synthase. It mediates signaling by insulin and other growth factors and nutrients, and it acts in the specification of cell fates during embryonic development. Among its targets are cytoskeletal proteins

15.4 Coordinated Regulation of Glycogen Synthesis and Breakdown 587

Active site

Priming site phosphorylated by casein kinase II

(—A SVPPSPSLSRHSSPHQSEDE E—) Glycogen

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