Determination of the mechanism of activation and the physiological functions of serum and glucocorticoid-regulated kinase-3.
Published: 2006
Language: eng
Number of pages: 144
ISBN-13: 9780494219263
Description: The phosphatidylinositol 3' kinase (P13K) pathway is an important signaling cascade that modulates several critical cellular processes including survival pathways. Several components of this pathway are recognized oncogenes and tumor suppressors, such as P13K catalytic subunits themselves, Protein Kinase B (PKB)/Akt and -PTEN, and they represent promising targets for cancer therapeutics. The Serum and Glucocorticoid-regulated kinase-3 (SGK3) is a novel component of the P13K pathway and exhibits structural similarity to PKB, contributing to its interest. The level of understanding of the regulation of SGK3 activity and its cellular roles has been very limited. Herein, we have studied and hence shed light on the mechanism of activation and the physiological functions of SGK3.We present a model of SGK3 regulation and compare its differences with PKB activation. We show that the Phox Homology (PX) phospholipid binding domain of SGK3 contributes to its activation by localising it to endosomes, where a P13K-dependent hydrophobic motif kinase phosphorylates it and yields a fully active SGK3. Our results indicate that SGK3, in addition to being involved in the P13K pathway, may also play an important role in cAMP responses. Microarray profiling of SGK3 null mouse embryonic fibroblasts revealed alterations in the gene expression profiles of Tenascin C (Tnc), solute carrier family 9 (sodium/hydrogen exchanger), isoform 3 regulator 1 (SIc9a3r1), Lymphocyte antigen 6 complex, locus E (Ly6e) and Guanine nucleotide binding protein, alpha 13 (Gna13), genes implicated in tumorigenesis and in T cell homeostasis. We have generated two models of transgenic mice expressing a constitutively active mutant of SGK3 in mammary epithelial cells and in T cells. Expression of the activated SGK3 transgene affects ductal branching morphogenesis and lumenal formation and delays involution due to decreased apoptosis in murine mammary glands. We also demonstrate that SGK3-PRK2 has oncogenic potential as the two founders of the MMTV lines developed mammary tumors at six months of age. Finally, in the T cell model, SGK3-PRK2 caused thymic hyperplasias by seven weeks of age and promoted inflammation as well as signs of autoimmune disease.
Notes: Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0103.

Thesis (Ph.D.)--University of Toronto, 2006.

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