Mechanism of Ceramide-Induced Activation of Protein Phosphatase 2A

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Publication Type thesis
School or College School of Medicine
Department Biochemistry
Author Narra, Krishna Kanth
Title Mechanism of Ceramide-Induced Activation of Protein Phosphatase 2A
Date 2010-01-25
Description Insulin resistance is one of the key diagnostic criteria of metabolic syndrome X and is a pathognomonic feature of type 2 diabetes. The association of these pathologies with obesity and the finding of elevated levels of free fatty acids in insulin resistant animal models and human subjects led to the hypothesis that accumulation of excess lipid in nonadipose tissue causes insulin resistance. Several studies showed persuasive evidence that ceramide mediates saturated fat-induced inhibition of insulin signaling. A number of signaling intermediates including Jun N-terminal Kinase (JNK), Mixed Lineage Kinase 3 (MLK3), Protein Kinase (PKCQ, Protein Kinase C6 (PKC0), and Protein Phosphatase 2A (PP2A) have been proposed to mediate ceramide-induced antagonism of insulin signaling. Nevertheless, the mechanisms by which these signaling molecules are acted upon by ceramide are not known. Our work focused on the role of PP2A in mediating ceramide-induced inhibition of insulin-stimulated phosphorylation of Akt. In this document we show evidence that ceramide does not activate PP2A by allosteric mechanism by using in vitro assays, knockdown and overexpression strategies. Further search for the mechanism revealed that ceramide induced cytoplasmic translocation of nuclear I2PP2A, a potent endogenous inhibitor of PP2A. Knocking down I2PP2A inhibited phosphorylation of Thr308 and not Ser473 of Akt in response to insulin stimulation. We propose that ceramide disrupts the interaction between I2PP2A and PP2A, thus relieving the inhibition on the phosphatase, which in turn dephosphorylates Thr308 of Akt.
Type Text
Publisher University of Utah
Subject Ceramides; Phosphoprotein; Enzyme Activation; Insulin Resistance
Subject MESH Ceramides; Phosphoproteins; Enzyme Activation; Insulin Resistance
Dissertation Institution University of Utah
Dissertation Name MS
Language eng
Relation is Version of Digital reproduction of “Mechanism of ceramide-induced activation of protein phosphatase 2A.” Spencer S. Eccles Health Sciences Library. Print version of ” Mechanism of ceramide-induced activation of protein phosphatase 2A.: available at J. Willard Marriott Library Special Collection. QP6.5 2009.N37
Rights Management © Krishna Kanth Narra
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Source Original: University of Utah Spencer S. Eccles Health Sciences Library
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