1

New proteins

Phosphorylated Elkl joins SRF to stimulate the transcription and translation of a set of genes needed for cell division.

ERK moves into the nucleus and phosphorylates nuclear transcription factors such as Elkl, activating them.

SH2 domain of Grb2 binds to CP -Tyr of IRS-l. Sos binds to Grb2, then to Ras, causing GDP release and GTP binding to Ras.

Activated Ras binds and activates Raf-1.

Raf-l phosphorylates MEK on two Ser residues, activating it. MEK phosphorylates ERK on a Thr and a Tyr residue, activating it.

FIGURE 12-6 Regulation of gene expression by insulin. The insulin receptor consists of two a chains on the outer face of the plasma membrane and two ß chains that traverse the membrane and protrude from the cytoplasmic face. Binding of insulin to the a chains triggers a conformational change that allows the autophosphorylation of Tyr residues in the carboxyl-terminal domain of the ß subunits. Autophosphorylation further activates the Tyr kinase domain, which then catalyzes phosphorylation of other target proteins. The signaling pathway by which insulin regulates the expression of specific genes consists of a cascade of protein kinases, each of which activates the next. The insulin receptor is a Tyr-specific kinase; the other kinases (all shown in blue) phosphorylate Ser or Thr residues. MEK is a dual-specificity kinase, which phosphorylates both a Thr and a Tyr residue in ERK (extracellular regulated kinase); MEK is mitogen-activated, ERK-activating kinase; SRF is serum response factor. Abbreviations for other components are explained in the text.

belongs to this family); and when a third kinase that activated MAP kinase kinase was discovered, it was given the slightly ludicrous family name MAP kinase kinase kinase (Raf-1 is a member of this family; Fig. 12-6). Slightly less cumbersome are the acronyms for these three families, MAPK, MAPKK, and MAPKKK. Kinases in the MAPK and MAPKKK families are specific for Ser or Thr residues, but MAPKKs (here, MEK) phosphorylate both a Ser and a Tyr residue in their substrate, a MAPK (here, ERK).

Biochemists now recognize the insulin pathway as but one instance of a more general theme in which hormone signals, via pathways similar to that shown in Figure 12-6, result in phosphorylation of target enzymes by protein kinases. The target of phosphorylation is often another protein kinase, which then phosphorylates a third protein kinase, and so on. The result is a cascade of reactions that amplifies the initial signal by many orders of magnitude (see Fig. 12-1b). Cascades such as that shown in Figure 12-6 are called MAPK cascades.

FIGURE 12-7 Activation of the insulin-receptor Tyr kinase by au-tophosphorylation. (a) In the inactive form of the Tyr kinase domain (PDB ID 1 IRK), the activation loop (blue) sits in the active site, and none of the critical Tyr residues (black and red ball-and-stick structures) are phosphorylated. This conformation is stabilized by hydrogen bonding between Tyr1162 and Asp1132. (b) When insulin binds to the a chains of insulin receptors, the Tyr kinase of each 3 subunit of the dimer phosphorylates three Tyr residues (Tyr1158, Tyr1162, and

Tyr1163) on the other 3 subunit (shown here; PDB ID 1IR3). (Phos-phoryl groups are depicted here as an orange space-filling phosphorus atom and red ball-and-stick oxygen atoms.) The effect of introducing three highly charged (p-Tyr residues is to force a 30 A change in the position of the activation loop, away from the substrate-binding site, which becomes available to bind to and phosphorylate a target protein, shown here as a red arrow.

FIGURE 12-7 Activation of the insulin-receptor Tyr kinase by au-tophosphorylation. (a) In the inactive form of the Tyr kinase domain (PDB ID 1 IRK), the activation loop (blue) sits in the active site, and none of the critical Tyr residues (black and red ball-and-stick structures) are phosphorylated. This conformation is stabilized by hydrogen bonding between Tyr1162 and Asp1132. (b) When insulin binds to the a chains of insulin receptors, the Tyr kinase of each 3 subunit of the dimer phosphorylates three Tyr residues (Tyr1158, Tyr1162, and

Tyr1163) on the other 3 subunit (shown here; PDB ID 1IR3). (Phos-phoryl groups are depicted here as an orange space-filling phosphorus atom and red ball-and-stick oxygen atoms.) The effect of introducing three highly charged (p-Tyr residues is to force a 30 A change in the position of the activation loop, away from the substrate-binding site, which becomes available to bind to and phosphorylate a target protein, shown here as a red arrow.

Grb2 is not the only protein that associates with phosphorylated IRS-1. The enzyme phosphoinositide 3-kinase (PI-3K) binds IRS-1 through the former's SH2 domain (Fig. 12-8). Thus activated, PI-3K converts the membrane lipid phosphatidylinositol 4,5-bisphosphate (see Fig. 10-15), also called PIP2, to phosphatidylinositol 3,4,5-trisphosphate (PIP3). When bound to PIP3, protein kinase B (PKB) is phosphorylated and activated by yet another protein kinase, PDK1. The activated PKB then phosphorylates Ser or Thr residues on its target proteins, one of which is glycogen synthase kinase 3 (GSK3). In its active, nonphosphorylated form, GSK3 phosphorylates glycogen synthase, inactivating it and thereby contributing to the slowing of glycogen synthesis. (This mechanism is believed to be only part of the explanation for the effects of insulin on glycogen metabolism.) When phosphorylated by PKB, GSK3 is inactivated. By thus preventing inactivation of glycogen synthase in liver and muscle, the cascade of protein phosphorylations initiated by insulin stimulates glycogen synthesis (Fig. 12-8). In muscle, PKB triggers the movement of glucose transporters (GLUT4) from internal vesicles to the plasma membrane, stimulating glucose uptake from the blood (Fig. 12-8; see also Box 11-2). PKB also functions in several other signaling pathways, including that triggered by A9-tetrahydro-cannabinol (THC), the active ingredient of marijuana

Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook


Post a comment