Class Ia phosphoinositide 3-kinases (PI3Ks) mediate cell and tissue growth downstream of insulin, IGF-1 and other growth factors. Impairments in the ability of insulin to stimulate PI3K in liver and muscle results in insulin resistance and type 2 diabetes, while genetic aberrations that result in hyper-activation of PI3K in epithelial tissues results in cancers. Activating mutations in PIK3CA, the gene encoding the p110 catalytic subunit of PI3K, are among the most frequent oncogenic occurrences in epithelial cancers, and inactivating mutations in PTEN, the phosphatase that degrades the lipid product of PI3K is among the most frequent tumor suppressor mutations. Previous research funded by this grant has helped to elucidate the biochemical mechanism by which PI3Ks are activated downstream of insulin and other growth factors and to define the downstream signaling pathway that control cell growth. However, much remains to be discovered. During the next granting period we will attempt to explain some recent surprising discoveries about regulation of PI3K in disease states.
The first aim i s evaluate the role of the PI-3, 4-P2 4-phosphatase, INPP4B in cellular regulation and tumor formation. During the previous granting period we discovered that INPP4B acts as a tumor suppressor in breast and ovarian cancers by dephosphorylating the lipid, PI-3, 4-P2. We will characterize mice with germline deleted and floxed-INPP4B in regard to tumor formation in the context of BRCA1 and TP53 deletions. We have also observed dramatic enhancement in macrophage phagocytosis in the INPP4B knockout mice and will further characterize the role of INPP4B in macrophage biology.
The second aim i s to evaluate the role of the p85 subunit of Class 1a PI3Ks in BRD7 function. Recently we discovered that the regulatory subunit of PI3K (p85 ) forms a tight complex with the bromo-domain protein, BRD7, a protein that mediates p53- dependent stress responses. We will further characterize the BRD7/p85 complex and determine its role in p53 and swi/snf regulation of gene expression.
The final aim i s to evaluate the role of novel mutations in PIK3CA and PIK3R1 in endometrial cancers. We and others have found that while breast cancer have very high rates of mutations in the catalytic and helical domains of PIK3CA (H1047R and E545K) endometrial cancers have unusually high rates of mutations in the N-terminal p85-binding domain of PIK3CA (especially R88Q), an event rarely seen in breast cancer. Endometrial cancers also have frequent mutations in the gene encoding p85 (PIK3R1). We will attempt to understand the biochemical mechanism by which these mutations contribute to endometrial cancers.
Defects in insulin-dependent stimulation of Phosphoinositide 3-Kinase (PI3K) result in insulin resistance and type 2 diabetes while activating mutations in PI3K result in cancers. More than twenty investigational drugs that target PI3K are currently in cancer clinical trials. The goal of this grant is to understand how PI3K is activated by insulin an growth factors and to determine how mutations in the gene encoding PI3K cause cancer.
|Hu, Hai; Juvekar, Ashish; Lyssiotis, Costas A et al. (2016) Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. Cell 164:433-46|
|Mayer, Ingrid A; Abramson, Vandana G; Formisano, Luigi et al. (2016) A Phase Ib Study of Alpelisib (BYL719), a PI3KÎ±-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res :|
|Lien, Evan C; Lyssiotis, Costas A; Cantley, Lewis C (2016) Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer. Recent Results Cancer Res 207:39-72|
|Wang, Yubao; Begley, Michael; Li, Qing et al. (2016) Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival. Proc Natl Acad Sci U S A 113:9810-5|
|Juvekar, Ashish; Hu, Hai; Yadegarynia, Sina et al. (2016) Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc Natl Acad Sci U S A 113:E4338-47|
|Breitkopf, Susanne B; Yang, Xuemei; Begley, Michael J et al. (2016) A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2. Sci Rep 6:20471|
|Lien, Evan C; Lyssiotis, Costas A; Juvekar, Ashish et al. (2016) Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat Cell Biol 18:572-8|
|Shim, Hyeseok; Wu, Chuan; Ramsamooj, Shivan et al. (2016) Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system. Proc Natl Acad Sci U S A 113:7596-601|
|Liu, Pengda; Gan, Wenjian; Chin, Y Rebecca et al. (2015) PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex. Cancer Discov 5:1194-209|
|Dibble, Christian C; Cantley, Lewis C (2015) Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 25:545-55|
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