Dual Regulation of Platelet Protein Kinase B

Kroner, Christine; Eybrechts, Kurt; Akkerman, Jan-Willem Ν.

doi:10.1074/jbc.m000540200

Cited by 124 publications

(163 citation statements)

References 42 publications

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“…In thrombin-treated platelets, a conventional PKC inhibitor also prevented pAktS473, although the effect was only partial and a co-factor was probably necessary. 40 Because our activity assays were performed with PKC-␤1 immunoprecipitated from MC under various conditions, we cannot exclude requirement for a co-factor when PKC-␤1 functions as an AktS473 kinase.…”

Section: Discussionmentioning

confidence: 99%

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Peng²,

Zhang³

et al. 2009

Journal of the American Society of Nephrology

102

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Accumulation of glomerular matrix is a hallmark of diabetic nephropathy. The serine/threonine kinase Akt mediates glucose-induced upregulation of collagen I in mesangial cells through transactivation of the EGF receptor (EGFR). In addition, in renal tubular cells, glucose-induced secretion of TGF-␤ requires phosphoinositide-3-OH kinase, suggesting a possible role for Akt in the modulation of TGF-␤ expression, but the mechanisms of Akt activation and its involvement in TGF-␤ regulation are unknown. Here, in primary mesangial cells, high glucose induced AktS473 phosphorylation, which correlates with its activation, in a protein kinase C ␤ (PKC-␤)-dependent manner. Glucose led to PKC-␤1 membrane translocation and association with Akt, and PKC-␤1 immunoprecipitated from glucose-treated cells phosphorylated recombinant Akt on S473. PKC is known to mediate glucose-induced TGF-␤1 upregulation through the transcription factor AP-1; here, inhibitors of phosphoinositide-3-OH kinase, PKC-␤ and Akt, and dominant-negative Akt all prevented glucose-induced activation of AP-1 and upregulation of TGF-␤1. Finally, pharmacologic and dominant negative inhibition of EGFR blocked glucose-induced activation of PKC-␤1, phosphorylation of AktS473, activation of AP-1, and upregulation of TGF-␤1. In vivo, the PKC-␤ inhibitor ruboxistaurin prevented Akt activation in the renal cortex of diabetic rats. In conclusion, PKC-␤1 is an Akt S473 kinase in glucose-treated mesangial cells, and TGF-␤1 transcriptional upregulation requires EGFR/PKC-␤1/Akt signaling. New therapeutic approaches for diabetic nephropathy may result from targeting components of this pathway, particularly the initial EGFR transactivation. 20: 554 -566, 200920: 554 -566, . doi: 10.1681 The kidney is an important site of diabetic microvascular complications, and hyperglycemia is central to glomerular matrix accumulation. Although strict glucose control and inhibition of the reninangiotensin system are effective in delaying the development of nephropathy, disease progression often occurs. The development of new treatment approaches is thus an important goal. J Am Soc NephrolWe have shown that collagen I induction by high glucose (HG) requires activation of the serine/threonine kinase Akt, and this depends on transactivation of the EGF receptor (EGFR). 1 Akt activation requires membrane translocation and phosphorylation on two sites, S473 and T308. 2 Phosphoinositide-3-OH kinase (PI3K) is an upstream mediator of Akt activation, generating phosphorylated lipid second messengers that recruit proteins with pleckstrin homology domains such as Akt to the membrane. 3 At the membrane, phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates Akt at T308. 3 Several S473 kinases, however, have

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Section: Discussionmentioning

confidence: 99%

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Peng²,

Zhang³

et al. 2009

Journal of the American Society of Nephrology

102

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“…Balendran et al [29] have shown that 3-phosphoinositide-dependent protein kinase-1, Akt and protein-kinase-C-related kinase-2 interact with each other after the phosphorylation of Thr308, which can be converted into 3-phosphoinositide-dependent protein kinase-2 (PDK2) and modify Ser473. Kroner et al [30] have found that the existence of PDK2 can be proven by the complex relationship between Thr308 and Ser473, which is phosphorylated independently. A study by Ferguson et al [31] has shown that Akt can be activated in a PI3-K-independent pathway.…”

Section: Discussionmentioning

confidence: 99%

Signal transduction mechanism of TRB3 in rats with non-alcoholic fatty liver disease

Wang¹,

Shi²,

Wang³

et al. 2009

WJG

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AIM:To evaluate the possible role of Tribble 3 (TRB3) in a rat model of non-alcoholic fatty liver disease (NAFLD) and its signal transduction mechanism.METHODS: T h i r ty S p ra g u e -D a w l e y ra t s w e r e randomized into three groups: normal control group, non-alcoholic fatty liver group A (fed on a highfat diet for 8 wk) and group B (fed on a high-fat diet for 16 wk). To determine the degree of hepatic steatosis in rats of each group, livers were stained with hematoxylin and eosin, and evaluated; realtime fluorescent quantitative reverse transcriptasepolymerase chain reaction was performed to measure the expression levels of TRB3 mRNA; and Western blotting analysis was done to determine the expression levels of protein kinase B (Akt) and phosphorylated protein kinase B (p-Akt-Thr308, p-Akt-Ser473). RESULTS:Hepatic steatosis was evident in both NAFLD groups: mild to moderate hepatic steatosis occurred in group A, mainly as mild steatosis. Moderate to severe hepatic steatosis occurred in group B, mainly as severe steatosis. The expression level of TRB3 mRNA in group B was significantly higher than in the control group (122.28 ± 95.37 vs 3.06 ± 2.33, P = 0.001) and group A (122.28 ± 95.37 vs 5.77 ± 4.20, P = 0.001). There was no significant difference in the CONCLUSION: TRB3 blocks insulin signaling by inhibiting Akt activation, which contributes to insulin resistance. It may be an important factor in the occurrence and development of NAFLD.

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“…ILK is a viable candidate because depletion of ILK in HEK-293 cells with the use of siRNA almost completely inhibits Ser 473 phosphorylation (24), although it is presently unknown whether ILK exerts these effects directly or via an intermediate kinase. Finally, in platelets, activation of PKC can phosphorylate Akt on Ser 473 in a PI3-K-independent manner (14). This is unlikely to be the case in VSMCs, however, because ANG II-induced activation of Akt is PI3-K-dependent (26), as it is for most other agonists and cell types (15).…”

Section: Discussionmentioning

confidence: 99%

Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Taniyama¹,

Ushio‐Fukai²,

Hitomi³

et al. 2004

American Journal of Physiology-Cell Physiology

112

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II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser 473 , but not Thr 308 . Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Aktp38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser 473 . These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROSsensitive signaling in VSMCs.mitogen-activated protein kinase; reactive oxygen species ANG II IS A PEPTIDE HORMONE that stimulates a plethora of signaling pathways, leading to cell growth and contraction. On binding to its receptor, the ANG II type 1 receptor, ANG II activates an array of protein kinases important for its growthpromoting effects. These kinases include c-Src (11), epidermal growth factor receptor (8), ERK1/2 (7), p38 MAPK (25), and Akt/protein kinase B (26). Activation of p38 MAPK and Akt requires the production of reactive oxygen species (ROS), whereas ERK1/2 stimulation is independent of ROS (25). Our laboratory has previously shown that all three of these kinases mediate ANG II-induced vascular smooth muscle cell (VSMC) hypertrophy (25,26); however, the relationship between the ROS-sensitive kinases p38 MAPK and Akt is unclear.Although it has been clearly shown that activation of Akt requires phosphatidylinositol 3-kinase (PI3-K) activity and NAD(P)H oxidase-derived production of ROS (6, 26), the full complement of upstream mediators of Akt activation by ANG II is not yet fully understood. Akt activation requires phosphorylation of two amino acid residues by upstream kinases: threonine 308 (Thr 308 ) by 3-phosphoinositide-dependent protein kinase (PDK)-1 and serine 473 (Ser 473 ) by a "so-called" PDK2, whose identity is controversial (4). To date, five kinases have been proposed as candidates for PDK2: Akt itself, PDK1, integrin-linked kinase...

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Dual Regulation of Platelet Protein Kinase B

Cited by 124 publications

References 42 publications

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Signal transduction mechanism of TRB3 in rats with non-alcoholic fatty liver disease

Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

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