Class I phosphoinositide 3-kinases (PI3Ks) are now known to regulate cell growth, cell metabolism, cell survival, cell cycle entry and cell movement. Insulin utilizes Class Ia PI3Ks for regulation of glucose homeostasis and impairment in this regulation can result in Type II diabetes. Activating mutations in Class Ia PI3Ks or inactivating mutations in PTEN, a phosphatase that degrades PI3K products, are some of the most frequent events in human cancers and the majority of solid tumors have mutations in some component of the PI3K signaling pathway. PI3K inhibitors are now in clinical trials for treating cancers and for immune suppression and there is optimism about potential benefits, but concern about potential adverse affects. Over the past granting period we have attempted to understand the complex network of PI3K activation and downstream signaling using a combination of biochemical approaches, cell-based studies and mouse genome manipulations. While work from our laboratory and many other laboratories has resulted in considerable progress in understanding this complex signaling network over the past five years, it is clear that there is much to be done. Our goals for the next granting period are focused on uncovering the complexity of Class Ia PI3K regulation and downstream signaling. We will investigate the relative roles of PI-3,4-P2 and PI-3,4,5-P3 in cellular regulation. We have recently found that a phosphatases that degrades PI-3,4-P2 is a tumor suppressor in human solid tumors suggesting that this lipid plays an important role in cell transformation. We will also determine the mechanism by which the p85 regulatory subunit controls Class Ia PI3K signaling. In particular, we will investigate the importance of post-translational modifications we have recently identified on p85alpha. Finally, we will investigate stochastic regulation of the PI3K pathway in epithelial cells.
The PI3K pathway is the most frequently mutated pathway in human cancers. This grant has funded the research that led to the discovery and elucidation of this pathway. The goal of the proposed research is to identify key regulatory components of this pathway in order to uncover new targets for pharmaceutical intervention.
|Chiu, Yu-Hsin; Lee, Jennifer Y; Cantley, Lewis C (2014) BRD7, a tumor suppressor, interacts with p85? and regulates PI3K activity. Mol Cell 54:193-202|
|Fruman, David A; Cantley, Lewis C (2014) Idelalisib--a PI3K? inhibitor for B-cell cancers. N Engl J Med 370:1061-2|
|Park, Sang Won; Herrema, Hilde; Salazar, Mario et al. (2014) BRD7 regulates XBP1s' activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K. Cell Metab 20:73-84|
|Liu, Pengda; Begley, Michael; Michowski, Wojciech et al. (2014) Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 508:541-5|
|Mayer, Ingrid A; Abramson, Vandana G; Isakoff, Steven J et al. (2014) Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 32:1202-9|
|Menon, Suchithra; Dibble, Christian C; Talbott, George et al. (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771-85|
|González-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung et al. (2014) Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov 4:896-904|
|Davis, Mindy I; Sasaki, Atsuo T; Shen, Min et al. (2013) A homogeneous, high-throughput assay for phosphatidylinositol 5-phosphate 4-kinase with a novel, rapid substrate preparation. PLoS One 8:e54127|
|Gallop, Jennifer L; Walrant, Astrid; Cantley, Lewis C et al. (2013) Phosphoinositides and membrane curvature switch the mode of actin polymerization via selective recruitment of toca-1 and Snx9. Proc Natl Acad Sci U S A 110:7193-8|
|Baker, Rachael; Lewis, Steven M; Sasaki, Atsuo T et al. (2013) Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function. Nat Struct Mol Biol 20:46-52|
Showing the most recent 10 out of 112 publications