Lipin- A Novel of the Insulin/mTOR Signaling Pathway

Huffman, Todd Aaron, Department of Pharmacology, University of Virginia
Lawrence, John, Department of Pharmacology, University of Virginia
Garrison, Jim, Department of Pharmacology, University of Virginia
Sturgill, Thomas, Department of Pharmacology, University of Virginia
Keller, Susanna, Department of Medicine, Endocrinology and Metabolism, University of Virginia

Signal transduction, initiated by the binding of insulin to its membrane receptor, is mediated by a complex network of molecular cascades. Covalent phosphorylation of proteins, catalyzed by protein kinases, is the predominant mechanism by which these cascades propagate signal. Activation of the insulin signaling pathway results in glucose utilization, glycogen synthesis, protein synthesis, and alterations in triglyceride metabolism. Insults to this pathway, genetic or environmental, result in insulin resistance, a hallmark aspect of type 2 diabetes mellitus and lipodystrophy. The present work expands our knowledge of insulin action by identifying and partially characterizing two targets of the insulin signaling pathway. One of these targets, Isp62, had been described previously as an insulin-sensitive phosphoprotein, but with undefined primary sequence (146). Here we provide data indicating that this protein is PKB/Akt2, a known member of the insulin signaling pathway. In a separate investigation a novel protein, lipin, was identified, and found to be phosphorylated acutely in response to insulin. Lipin is the product of a gene mutated in a mouse model of lipodystrophy called fatty liver dystrophy (fld). Mice harboring this mutation exhibit phenotypic abnormalities including insulin resistance, glucose intolerance, and undifferentiated adipose tissue (91). In adipocytes, insulin-stimulated phosphorylation of lipin was inhibited by pretreatment with rapamycin, implicating the mammalian target of rapamycin (mTOR) in the control of this process. Additional investigations distinguished more than 20 sites of phosphorylation in lipin. Of these sites, Serine-106, was found to be a target of insulinstimulated phosphorylation, prompting the hypothesis that this residue represents a critical element linking insulin action to a yet undefined lipin activity. Collectively, these findings expand our understanding of insulin action and tentatively link insulin 4 signaling via mTOR to the regulation of adipocyte development.

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PHD (Doctor of Philosophy)
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