A New Molecular Target of Insulin Action: Regulating the Pivotal PDK1

Wick, K. L.; Liu, Feng

doi:10.2174/1568008013341082

Cited by 27 publications

(25 citation statements)

References 97 publications

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“…PDK1 activation depends on binding to PIP 3 in the context of the plasma membrane. It is possible that PDK1 is mislocated and therefore misregulated in diabetic endothelial cells (35). It is also possible that the multiple PDK isoforms, such as PDK2, with select tissue distribution may contribute to the diversified actions of insulin signaling in different tissue (35).…”

Section: Discussionmentioning

confidence: 99%

Altered Insulin Signaling in Retinal Tissue in Diabetic States

Kondo

Kahn

2004

Journal of Biological Chemistry

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Both type 1 and type 2 diabetes can lead to altered retinal microvascular function and diabetic retinopathy. Insulin signaling may also play a role in this process, and mice lacking insulin receptors in endothelial cells are protected from retinal neovascularization. To define the role of diabetes in retinal function, we compared insulin signaling in the retinal vasculature of mouse models of type 1 (streptozotocin) and type 2 diabetes (ob/ob). In streptozotocin mice, in both retina and liver, insulin receptor (IR) and insulin receptor substrate (IRS)-2 protein and tyrosine phosphorylation were increased by insulin, while IRS-1 protein and its phosphorylation were maintained. By contrast, in ob/ob mice, there was marked down-regulation of IR, IRS-1, and IRS-2 protein and phosphorylation in liver; these were maintained or increased in retina. In both mice, Phosphatidylinositol 3,4,5-trisphosphate generation by acute insulin stimulation was enhanced in retinal endothelial cells. On the other hand, protein levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice. Interestingly, phosphorylation of p38 mitogen-activated protein kinase and ERK1 were responsive to insulin in retina of both mice but were unresponsive in liver. HIF-1␣ and vascular endothelial growth factor were increased and endothelial nitric-oxide synthase was decreased in retina. These observations indicate that, in both insulin-resistant and insulin-deficient diabetic states, there are alterations in insulin signaling, such as impaired PDK/Akt responses and enhanced mitogen-activated protein kinases responses that could contribute to the retinopathy. Furthermore, insulin signaling in retinal endothelial cells is differentially altered in diabetes and is also differentially regulated from insulin signaling in classical target tissues such as liver.

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Section: Discussionmentioning

confidence: 99%

Altered Insulin Signaling in Retinal Tissue in Diabetic States

Kondo

Kahn

2004

Journal of Biological Chemistry

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“…PDK1 phosphorylates many important cellular kinases such as protein kinase B (Akt/PKB), PKC isoforms, and p70 S6 kinase in the activation loop and contributes to their activation in a PI 3-kinase-dependent manner. These results suggest that PDK1 may play a key role in the regulation of various cellular events such as cell proliferation, differentiation, and apoptosis (1,2).…”

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confidence: 91%

Mouse 3-Phosphoinositide-dependent Protein Kinase-1 Undergoes Dimerization and trans-Phosphorylation in the Activation Loop

Wick

Ramos

Chen

et al. 2003

Journal of Biological Chemistry

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Activation of mouse 3-phosphoinositide-dependent protein kinase-1 (mPDK1) requires phosphorylation at a conserved serine residue, Ser 244 , in the activation loop. However, the mechanism by which mPDK1 is phosphorylated at this site remains unclear. We have found that kinase-defective mPDK1 (mPDK1 KD ), but not a kinasedefective mPDK1 in which Ser 244 was replaced with alanine (mPDK1 KD/S244A ), is significantly phosphorylated in intact cells and is a direct substrate of wild-type mPDK1 fused to the yellow fluorescence protein. Phosphoamino acid analysis and phosphopeptide mapping studies revealed that mPDK1 trans-autophosphorylation occurred mainly on Ser 244 . On the other hand, Ser 399 and Thr 516 , two recently identified autophosphorylation sites of mPDK1, are phosphorylated primarily through a cis mechanism. In vivo labeling studies revealed that insulin stimulated both mPDK1 KD and mPDK1 KD/S244A phosphorylation in Chinese hamster ovary cells overexpressing the insulin receptor. However, Western blot analysis using a phosphospecific antibody revealed no increase in insulin-stimulated phosphorylation of Ser 244 in these cells overexpressing mPDK1. mPDK1 undergoes dimerization in cells and this self-association is enhanced by kinase inactivation. Deletion of the extreme C terminus disrupts mPDK1 dimerization and Ser 244 trans-phosphorylation, suggesting that dimerization is important for mPDK1 transphosphorylation. Taken together, our results show that mPDK1 autophosphorylation occurs at multiple sites through both cis and trans mechanisms and suggest that dimerization and trans-phosphorylation may serve as mechanisms to regulate PDK1 activity in cells.3-Phosphoinositide-dependent protein kinase-1 (PDK1) 1 is a serine/threonine kinase that acts downstream of PI 3-kinase in insulin and IGF-1 signaling pathways. PDK1 phosphorylates many important cellular kinases such as protein kinase B (Akt/PKB), PKC isoforms, and p70 S6 kinase in the activation loop and contributes to their activation in a PI 3-kinase-dependent manner. These results suggest that PDK1 may play a key role in the regulation of various cellular events such as cell proliferation, differentiation, and apoptosis (1, 2).While PDK1 has been shown to activate PKB/Akt and its other substrates by catalyzing the phosphorylation of a conserved residue in the activation loop of these kinases, how PDK1 itself is regulated remains largely unknown. Recent studies suggest that phosphorylation may play a role in the regulation of PDK1 function in cells (3). Multiple phosphorylation sites have been identified on PDK1 and several heterologous kinases that mediate some of these phosphorylation events have been identified. Src, Fyn, and Abl tyrosine kinases can phosphorylate PDK1 in vitro and overexpression of v-Src results in tyrosine phosphorylation of PDK1 in cells (4 -6). Specific serine/threonine kinases that phosphorylate PDK1 have not been identified. However, PDK1 has been shown to possess the intrinsic ability to phosphorylate itself (7,8).The mechanism ...

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“…PIP3 levels are low in resting cells but are acutely increased in response to multiple stimuli that activate PI3K (20). On one hand, this leads to the recruitment and activation of PDK-1, which in turn regulates the phosphorylation of several members of the AGC kinase family, including p70 ribosomal protein S6 kinase (p70S6K), serum and glucocorticoid-inducible kinase (SGK), protein kinase C (PKC) isoforms, p90 ribosomal S6 kinase (RSK), protein kinase C-related kinases 1 and 2 (PRK1/2), and p21-activated kinase 1 (PAK1) at the residue Thr308 equivalent of AKT (49,58). On the other hand, in other cell types, PIP3 can also propagate signals independently of PDK-1-mediated kinase activation, such as the regulation of ATP-sensitive potassium (K ATP ) channels and actin cytoskeleton degradation (47,48).…”

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confidence: 99%