Insulin activates protein kinase B, inhibits glycogen synthase kinase‐3 and activates glycogen synthase by rapamycin‐insensitive pathways in skeletal muscle and adipose tissue

Cross, Darren A.E.; Watt, Peter; Shaw, M.; Kaay, Jeroen van der; Downes, C P; Holder, Julie C.; Cohen, Philip

doi:10.1016/s0014-5793(97)00240-8

Cited by 198 publications

(163 citation statements)

References 31 publications

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“…This occurs via PKB inactivation of the kinase GSK3 (33,34) and has been thought to also involve activation of glycogen-bound PP-1 (PP-1G). The proposed mechanism for activation of PP-1G invoked selective phosphorylation of Ser 48 in the G M subunit, a model that has been influential for 10 years (11,18).…”

Section: Discussionmentioning

confidence: 99%

“…Although insulin has been reported to inhibit GSK-3 by phosphorylation via protein kinase B (33,34), inhibition of GSK-3 cannot account for the insulin stimulated dephosphorylation of all critical sites in glycogen synthase (49). Insulin was found to promote dephosphorylation of 5 sites in rabbit skeletal muscle glycogen synthase (52)(53)(54).…”

Section: Phosphorylation Of Full-length G M Site 1 and Site 2 In Livimentioning

confidence: 99%

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Insulin-stimulated Phosphorylation of the Protein Phosphatase-1 Striated Muscle Glycogen-targeting Subunit and Activation of Glycogen Synthase

Liu¹,

Brautigan

2000

Journal of Biological Chemistry

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Insulin stimulates glycogen synthesis in mammalian striated muscle by promoting the multisite dephosphorylation and activation of glycogen synthase, the rate-limiting enzyme in this process (1-3). Based on biochemical studies, glycogen synthase is inactivated primarily by cAMP-dependent protein kinase (PKA) 1 and glycogen synthase kinase-3 (GSK-3) that together phosphorylate 7 separate sites in glycogen synthase (4 -8), and activated by PP-1G, a glycogen-bound form of protein phosphatase-1 that shows specificity for dephosphorylation of these sites in glycogen synthase, relative to other substrates (9 -11). The subcellular location, substrate specificity, and regulation of PP-1 activity are determined by its interaction with targeting subunits. In skeletal and cardiac muscle the major glycogen-associated form of PP-1 (PP-1G) is a heterodimer composed of the phosphatase catalytic subunit (PP-1) and a subunit called G M or R Gl . G M directs PP-1 to glycogenprotein particles as well as membranes of the sarcoplasmic reticulum (11,12), by directly binding glycogen and by virtue of a putative transmembrane segment near the C terminus. This localization presumably facilitates the dephosphorylation of glycogen-metabolizing enzymes and sarcoplasmic reticulum proteins, such as phospholamban (11,(13)(14)(15).Since the discovery of G M a family of glycogen-targeting subunits have been found, and these are closely related in sequence to the N-terminal domain of G M . All members of this family bind glycogen and PP-1. Overexpression of one of these subunits, called PTG, promotes the activation of glycogen synthase (14). Curiously, although the structure and function seems to be conserved among this family of proteins, only G M is phosphorylated. Purified preparations of rabbit skeletal muscle G M were phosphorylated at Ser 48 (site 1) and Ser 67 (site 2) by PKA, which prevented binding of PP-1, as a possible way of reducing PP-1 activity toward glycogen-metabolizing enzymes (11, 16). As expected, phosphorylation of G M at both sites 1 and 2 occurs in intact muscle in response to adrenaline (17). However, the phosphorylation of G M in response to insulin, and the possible role of G M phosphorylation in activation of glycogen synthase, has been a subject of controversy for 10 years.Insulin reportedly increased phosphorylation of Ser 48 (site 1) in G M by activation of an insulin-stimulated protein kinase (18). Site 1 phosphorylation was said to produce a 2-fold increase in the PP-1G-catalyzed dephosphorylation of glycogen synthase (18). This offered a pathway for insulin activation of glycogen synthase, through site 1 phosphorylation of G M . With

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Section: Discussionmentioning

confidence: 99%

Section: Phosphorylation Of Full-length G M Site 1 and Site 2 In Livimentioning

confidence: 99%

Insulin-stimulated Phosphorylation of the Protein Phosphatase-1 Striated Muscle Glycogen-targeting Subunit and Activation of Glycogen Synthase

Liu¹,

Brautigan

2000

Journal of Biological Chemistry

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“…Data supporting a role for Akt include the fact that insulin administration in vivo in rats and humans rapidly activates Akt in skeletal muscle (19,20). The ability of Akt to inhibit glycogen synthase kinase-3 (19,21), a critical step in the activation of glycogen synthase by insulin, suggests a potential role for Akt in glycogen synthesis. In addition, Akt may regulate glycolysis via activation of phosphofructose 2-kinase (22).…”

Section: Divergent Regulation Of Akt1 and Akt2 Isoforms In Insulin Tamentioning

confidence: 99%

Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats.

et al. 2000

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To determine whether impaired Akt (protein kinase B or rac) activation contributes to insulin resistance in vivo, we examined the expression, phosphorylation, and kinase activities of Akt1 and Akt2 isoforms in insulin target tissues of insulin-resistant obese Zucker rats. In lean rats, insulin (10 U/kg i.v. ؋ 2.5 min) stimulated Akt1 activity 6.2-, 8.8-, and 4.4-fold and Akt2 activity 5.4-, 9.3-, and 1.8-fold in muscle, liver, and adipose tissue, respectively. In obese rats, insulin-stimulated Akt1 activity decreased 30% in muscle and 21% in adipose tissue but increased 37% in liver compared with lean littermates. Insulin-stimulated Akt2 activity decreased 29% in muscle and 37% in liver but increased 24% in adipose tissue. Akt2 protein levels were reduced 56% in muscle and 35% in liver of obese rats, but Akt1 expression was unaltered. Phosphoinositide 3-kinase (PI3K) activity associated with insulin receptor substrate (IRS)-1 or phosphotyrosine was reduced 67-86% in tissues of obese rats because of lower IRS-1 protein levels and reduced insulin receptor and IRS-1 phosphorylation. In adipose tissue of obese rats, in spite of an 86% reduction in insulinstimulated PI3K activity, activation of Akt2 was increased. Maximal insulin-stimulated (100 nmol/l) glucose transport was reduced 70% in isolated adipocytes, with a rightward shift in the insulin dose response for transport and for Akt1 stimulation but normal sensitivity for Akt2. These findings suggest that PI3K-dependent effects on glucose transport in adipocytes are not mediated primarily by Akt2. Akt1 and Akt2 activations by insulin have a similar time course and are maximal by 2.5 min in adipocytes of both lean and obese rats. We conclude that 1) activation of Akt1 and Akt2 in vivo is much less impaired than activation of PI3K in this insulin-resistant state, and 2) the mechanisms for divergent alterations in insulin action on Akt1 and Akt2 activities in tissues of insulinresistant obese rats involve tissue-and isoform-specific changes in both expression and activation. Diabetes 49:847-856, 2000

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“…For example, PKB has been implicated in insulin-stimulated translocation of GLUT4 transporter and glucose transport in rat adipocytes (4,5), insulin stimulation of glycogen synthesis (6,7), meiotic maturation of frog oocytes (8), and antiapoptotic actions of IGF-1 (9) and IL-3 (10,11).…”

Section: Cyclic Nucleotide Phosphodiesterase 3b Is a Downstream Targementioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterase 3B Is a Downstream Target of Protein Kinase B and May Be Involved in Regulation of Effects of Protein Kinase B on Thymidine Incorporation in FDCP2 Cells

Ahmad

Cong

Stenson

et al. 2000

The Journal of Immunology

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Wild-type (F/B), constitutively active (F/B*), and three kinase-inactive (F/Ba−, F/Bb−, F/Bc−) forms of Akt/protein kinase B (PKB) were permanently overexpressed in FDCP2 cells. In the absence of insulin-like growth factor-1 (IGF-1), activities of PKB, cyclic nucleotide phosphodiesterase 3B (PDE3B), and PDE4 were similar in nontransfected FDCP2 cells, mock-transfected (F/V) cells, and F/B and F/B− cells. In F/V cells, IGF-1 increased PKB, PDE3B, and PDE4 activities ∼2-fold. In F/B cells, IGF-1, in a wortmannin-sensitive manner, increased PKB activity ∼10-fold and PDE3B phosphorylation and activity (∼4-fold), but increased PDE4 to the same extent as in F/V cells. In F/B* cells, in the absence of IGF-1, PKB activity was markedly increased (∼10-fold) and PDE3B was phosphorylated and activated (3- to 4-fold); wortmannin inhibited these effects. In F/B* cells, IGF-1 had little further effect on PKB and activation/phosphorylation of PDE3B. In F/B− cells, IGF-1 activated PDE4, not PDE3B, suggesting that kinase-inactive PKB behaved as a dominant negative with respect to PDE3B activation. Thymidine incorporation was greater in F/B* cells than in F/V cells and was inhibited to a greater extent by PDE3 inhibitors than by rolipram, a PDE4 inhibitor. In F/B cells, IGF-1-induced phosphorylation of the apoptotic protein BAD was inhibited by the PDE3 inhibitor cilostamide. Activated PKB phosphorylated and activated rPDE3B in vitro. These results suggest that PDE3B, not PDE4, is a target of PKB and that activated PDE3B may regulate cAMP pools that modulate effects of PKB on thymidine incorporation and BAD phosphorylation in FDCP2 cells.

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Insulin activates protein kinase B, inhibits glycogen synthase kinase‐3 and activates glycogen synthase by rapamycin‐insensitive pathways in skeletal muscle and adipose tissue

Cited by 198 publications

References 31 publications

Insulin-stimulated Phosphorylation of the Protein Phosphatase-1 Striated Muscle Glycogen-targeting Subunit and Activation of Glycogen Synthase

Insulin-stimulated Phosphorylation of the Protein Phosphatase-1 Striated Muscle Glycogen-targeting Subunit and Activation of Glycogen Synthase

Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats.

Cyclic Nucleotide Phosphodiesterase 3B Is a Downstream Target of Protein Kinase B and May Be Involved in Regulation of Effects of Protein Kinase B on Thymidine Incorporation in FDCP2 Cells

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