Coordinated Regulation of Glycogen Synthesis and Breakdown:- Glycogen Synthase Kinase 3 Mediates the Actions of Insulin
one way in which insulin triggers intracellular changes is by activating a protein ki nase (protein kinase B, or PKB) that in turn phosphorylates 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 dephosphorylation of glycogen synthase by PP1. Glycogen phos phorylase can also affect the phosphorylation of glycogen synthase: active glycogen phosphorylase directly inhibits PP1, preventing it from activating glycogen synthase (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 and proteins essential for mRNA and protein synthesis. These targets, like glycogen synthase, must first undergo a priming phosphorylation by another protein ki nase before they can be phosphorylated by GSK3.
FIGURE 15–28 Priming of GSK3 phosphorylation of glycogen synthase. (a) Glycogen synthase kinase 3 first associates with its substrate (glycogen synthase) by interaction between three positively charged residues (Arg96, Arg180, Lys205) and a phosphoserine residue at position 4 in the substrate. (For orientation, the Ser or Thr residue to be phosphorylated in the substrate is assigned the index 0. Residues on the amino-terminal side of this residue are numbered -1, -2, and so forth; residues on the carboxyl-terminal side are numbered +1, +2, and so forth.) This association aligns the active site of the enzyme with a Ser residue at position 0, which it phosphorylates. This creates a new priming site, and the enzyme moves down the protein to phosphory late the Ser residue at position 4, and then the Ser at 8. (b) GSK3 has a Ser residue near its amino terminus that can be phosphorylated by PKA or PKB (see Fig. 15–29). This produces a “pseudosubstrate” region in GSK3 that folds into the priming site and makes the active site inaccessible to another protein substrate, inhibiting GSK3 until the priming phosphoryl group of its pseudosubstrate region is removed by PP1. Other proteins that are substrates for GSK3 also have a priming site at position +4, which must be phosphorylated by another protein kinase before GSK3 can act on them.
FIGURE 15–29 The path from insulin to GSK3 and glycogen synthase. Insulin binding to its receptor activates a tyrosine protein ki nase in the receptor, which phosphorylates insulin receptor substrate-1 (IRS-1). The phosphotyrosine in this protein is then bound by phosphatidylinositol 3-kinase (PI-3K), which converts phosphatidylinositol 4,5-bisphosphate (PIP2) in the membrane to phosphatidylinositol 3,4,5-trisphosphate (PIP3). A protein kinase (PDK-1) that is activated when bound to PIP3 activates a second protein kinase (PKB), which phosphorylates glycogen synthase kinase 3 (GSK3) in its pseudosubstrate region, inactivating it by the mechanisms shown in Figure 15–28b. The inactivation of GSK3 allows phosphoprotein phosphatase 1 (PP1) to dephosphorylate glycogen synthase, converting it to its active form. In this way, insulin stimulates glycogen synthesis. (See Fig. 12–8 for more details on insulin action.)
