In Vivo Adenoviral Delivery of Recombinant Human Protein Kinase C-ζ Stimulates Glucose Transport Activity in Rat Skeletal Muscle

Etgen, Garret J.; Valasek, Kathleen M.; Broderick, Carol L.; Miller, Anne Reifel

doi:10.1074/jbc.274.32.22139

Cited by 58 publications

(35 citation statements)

References 31 publications

(30 reference statements)

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“…They are activated by insulin through a PI3K-dependent mechanism (27,38), and insulin-stimulated glucose transport depends upon the activation of one or both of these enzymes (27,28,38,39). In the present study we provide evidence that PKC also plays a major regulatory role in a negative feedback control mechanism induced by insulin to terminate its own signaling pathways.…”

Section: Discussionsupporting

confidence: 49%

Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)

Liu

Paz

Herschkovitz

et al. 2001

Journal of Biological Chemistry

156

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Incubation of rat hepatoma Fao cells with insulin leads to a transient rise in Tyr phosphorylation of insulin receptor substrate (IRS) proteins. This is followed by elevation in their P-Ser/Thr content, and their dissociation from the insulin receptor (IR). Wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, abolished the increase in the P-Ser/Thr content of IRS-1, its dissociation from the IR, and the decrease in its P-Tyr content following 60 min of insulin treatment, indicating that the Ser kinases that negatively regulate IRS-1 function are downstream effectors of PI3K. PKC fulfills this criterion, being an insulin-activated downstream effector of PI3K. Overexpression of PKC in Fao cells, by infection of the cells with adenovirus-based PKC construct, had no effect on its own, but it accelerated the rate of insulin-stimulated dissociation of IR⅐IRS-1 complexes and the rate of Tyr dephosphorylation of IRS-1. The insulin-stimulated negative regulatory role of PKC was specific and could not be mimic by infecting Fao cells with adenoviral constructs encoding for PKC ␣, ␦, or . Because the reduction in P-Tyr content of IRS-1 was accompanied by a reduced association of IRS-1 with p85, the regulatory subunit of PI3K, it suggests that this negative regulatory process induced by PKC, has a built-in attenuation signal. Hence, insulin triggers a sequential cascade in which PI3K-mediated activation of PKC inhibits IRS-1 functions, reduces complex formation between IRS-1 and PI3K, and inhibits further activation of PKC itself. These findings implicate PKC as a key element in a multistep negative feedback control mechanism of IRS-1 functions.The insulin receptor mediates insulin action through the phosphorylation of substrate proteins on Tyr residues (1-3). The major substrates of the insulin receptor kinase are Shc (4) and the IRS 1 family of proteins, IRS-1 (5), IRS-2 (6), IRS-3 (7), and IRS-4 (8). IRS proteins contain a conserved PH (pleckstrin homology) domain (9, 10) located at the amino terminus, adjacent to a phosphotyrosine binding (PTB) domain. The PTB domain is present in a number of signaling molecules (11) and shares 75% sequence identity between IRS-1 and IRS-2 (12). This domain interacts with the NPXY motif of the juxtamembrane region of IR and promotes IR-IRS-1 interaction (13-15).The carboxyl-terminal region of IRS proteins is poorly conserved. It contains multiple tyrosine phosphorylation motifs that serve as docking sites for SH2 (Src homology-2) domaincontaining proteins like the p85␣ regulatory subunit of PI3K, Grb2, Nck, Crk, Fyn, and SHP-2, which mediate the metabolic and growth-promoting functions of insulin (1-3). IRS proteins contain more than 70 potential Ser/Thr phosphorylation sites for kinases like PKA (cAMP-dependent protein kinase), PKC, and MAPK (5, 6, 16). The phosphorylation of Ser/Thr residues of IRS proteins has a dual function, serving either for a positive or negative modulation of insulin signal transduction. Phosphorylation of Ser residues within the PTB domain of IRS-1 by ...

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Section: Discussionsupporting

confidence: 49%

Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)

Liu

Paz

Herschkovitz

et al. 2001

Journal of Biological Chemistry

156

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“…Along these lines, it should be noted that direct intramuscular. injection of adenovirus encoding wild-type aPKC leads to increases in insulin-stimulated glucose transport in rat muscles [31], and plasmid-and adenoviral-mediated increases in wild-type or constitutively active aPKC lead to increases in basal and insulinstimulated GLUT4 translocation and glucose transport in preparations of adipocytes and myocytes [29,30]. Thus, there is experimental evidence suggesting that increases in the availability of functionally active aPKC can enhance insulin effects on glucose transport in muscle.…”

Section: Discussionmentioning

confidence: 99%

Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

et al. 2006

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Aims/hypothesis: Metformin is widely used for treating type 2 diabetes mellitus, but its actions are poorly understood. In addition to diminishing hepatic glucose output, metformin, in muscle, activates 5'-AMP-activated protein kinase (AMPK), which alone increases glucose uptake and glycolysis, diminishes lipid synthesis, and increases oxidation of fatty acids. Moreover, such lipid effects may improve insulin sensitivity and insulinstimulated glucose uptake. Nevertheless, the effects of metformin on insulin-sensitive signalling factors in human muscle have only been partly characterised to date. Interestingly, other substances that activate AMPK, e.g., aminoimidazole-4-carboxamide-1-β-D-riboside (AICAR), simultaneously activate atypical protein kinase C (aPKC), which appears to be required for the glucose transport effects of AICAR and insulin. Methods: Since aPKC activation is defective in type 2 diabetes, we evaluated effects of metformin therapy on aPKC activity in muscles of diabetic subjects during hyperinsulinaemic-euglycaemic clamp studies. Results: After metformin therapy for 1 month, basal aPKC activity increased in muscle, with little or no change in insulin-stimulated aPKC activity. Metformin therapy for 8 to 12 months improved insulinstimulated, as well as basal aPKC activity in muscle. In contrast, IRS-1-dependent phosphatidylinositol (PI) 3-kinase activity and Ser473 phosphorylation of protein kinase B were not altered by metformin therapy, whereas the responsiveness of muscle aPKC to PI-3,4,5-(PO 4 ) 3 , the lipid product of PI 3-kinase, was improved. Conclusions/ interpretation: These findings suggest that the activation of AMPK by metformin is accompanied by increases in aPKC activity and responsiveness in skeletal muscle, which may contribute to the therapeutic effects of metformin.

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“…PKC-is an effector of PI 3-kinase signaling pathways that plays an important role in metabolic actions of insulin (1)(2)(3)(4). In addition, PKC-mediates a number of other biological actions of insulin, including activation of p70 S6 kinase (34), ERK2 (35), and NHE1 (36) and stimulation of protein synthesis (37).…”

Section: Discussionmentioning

confidence: 99%

“…1 is an atypical member of the protein kinase C family of Ser/Thr kinases that is an important mediator of the metabolic actions of insulin, such as translocation of the insulinresponsive glucose transporter GLUT4 and enhancement of glucose transport (1)(2)(3)(4). Activation of PKC-in response to insulin stimulation is regulated by PI 3-kinase-dependent pathways and involves PDK-1 phosphorylating Thr 410 in the PKC-activation loop (5,6).…”

Section: Pkc-mentioning

confidence: 99%

Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin

Ravichandran

Esposito

Chen

et al. 2001

Journal of Biological Chemistry

211

159

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Protein kinase C-(PKC-) is a serine/threonine kinase downstream from phosphatidylinositol 3-kinase in insulin signaling pathways. However, specific substrates for PKC-that participate in the biological actions of insulin have not been reported. In the present study, we identified insulin receptor substrate-1 (IRS-1) as a novel substrate for PKC-. Under in vitro conditions, wild-type PKC-(but not kinase-deficient mutant PKC-) significantly phosphorylated IRS-1. This phosphorylation was reversed by treatment with the serine-specific phosphatase, protein phosphatase 2A. In addition, the overexpression of PKC-in NIH-3T3 IR cells caused significant phosphorylation of cotransfected IRS-1 as demonstrated by [ P]orthophosphate labeling experiments. In rat adipose cells, endogenous IRS-1 coimmunoprecipitated with endogenous PKC-, and this association was increased 2-fold upon insulin stimulation. Furthermore, the overexpression of PKC-in NIH-3T3IR cells significantly impaired insulin-stimulated tyrosine phosphorylation of cotransfected IRS-1. Importantly, this was accompanied by impaired IRS-1-associated phosphatidylinositol 3-kinase activity. Taken together, our results raise the possibility that IRS-1 is a novel physiological substrate for PKC-. Because PKC-is located downstream from IRS-1 and phosphatidylinositol 3-kinase in established insulin signaling pathways, PKC-may participate in negative feedback pathways to IRS-1 similar to those described previously for Akt and GSK-3.

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In Vivo Adenoviral Delivery of Recombinant Human Protein Kinase C-ζ Stimulates Glucose Transport Activity in Rat Skeletal Muscle

Cited by 58 publications

References 31 publications

Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)

Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)

Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin

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