The long-term goal of this proposal is to understand the molecular, cellular and physiological mechanisms of signal termination mediated by the novel phosphatase PHLPP (PH domain Leucine- rich repeat Protein Phosphatase;pronounced 'flip') that we discovered. PHLPP terminates signaling by two oncogenic kinases, Akt and protein kinase C, by specifically dephosphorylating a key regulatory residue, the hydrophobic motif, which we originally identified on protein kinase C. PHLPP is frequently deleted in diverse human cancers and its deletion in mice promotes prostate tumors. Thus, the central hypothesis driving this proposal is that PHLPP terminates growth signaling pathways and that deregulation leads to pathophysiological states, notably cancer.
Three Aims are proposed: 1. Molecular Mechanisms of PHLPP. The goals are to identify small molecule inhibitors or activators of PHLPP to use as tools in cellular studies in Aims 2 and 3. In addition, we will test the hypothesis that cancer-associated mutations in PHLPP are inactivating and thus confer a survival advantage to tumor cells. 2. Cellular Mechanisms of PHLPP. The goal of this section is to understand the mechanisms that control the function of PHLPP in cells. First, we will use innovative live cell imaging technologies to test the hypothesis that spatial coordination on the PDZ scaffold NHERF increases the ability of PHLPP to control the amplitude and duration of Akt signaling. Second, we will address the mechanism by which PHLPP suppresses the levels of growth factor receptors in cells. 3. PHLPP in pathophysiology.
This Aim addresses the role of PHLPP in cancer. Specifically, we will test that hypothesis that deregulation of PHLPP by the E3 ligase 2-TrCP contributes to glioblastoma. In addition, we will address the roles of PHLPP1 and PHLPP2 in prostate cancer using a mouse model and in breast cell growth using a 3D culture model.

Public Health Relevance

This research is relevant to public health because it addresses the basic molecular mechanisms of cancer. Specifically, our lab discovered a new tumor suppressor that is frequently deleted in cancer and is poised as a novel and important therapeutic target. We would like to understand how to target this tumor suppressor in disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067946-11
Application #
8519126
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Chin, Jean
Project Start
2003-05-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$299,150
Indirect Cost
$106,150
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Reyes, Gloria; Niederst, Matt; Cohen-Katsenelson, Ksenya et al. (2014) Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output. Proc Natl Acad Sci U S A 111:E3957-65
Sierecki, Emma; Newton, Alexandra C (2014) Biochemical characterization of the phosphatase domain of the tumor suppressor PH domain leucine-rich repeat protein phosphatase. Biochemistry 53:3971-81
Newton, Alexandra C; Trotman, Lloyd C (2014) Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol 54:537-58
Wang, Pingping; Zhou, Zhihong; Hu, Anchang et al. (2014) Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt. Mol Cell 54:378-91
O'Neill, Audrey K; Niederst, Matthew J; Newton, Alexandra C (2013) Suppression of survival signalling pathways by the phosphatase PHLPP. FEBS J 280:572-83
Warfel, Noel A; Newton, Alexandra C (2012) Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP): a new player in cell signaling. J Biol Chem 287:3610-6
O'Hayre, M; Niederst, M; Fecteau, J F et al. (2012) Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL). Leukemia 26:1689-92
Warfel, Noel A; Niederst, Matt; Stevens, Michael W et al. (2011) Mislocalization of the E3 ligase, ýý-transducin repeat-containing protein 1 (ýý-TrCP1), in glioblastoma uncouples negative feedback between the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt. J Biol Chem 286:19777-88
Patterson, Scott J; Han, Jonathan M; Garcia, Rosa et al. (2011) Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. J Immunol 186:5533-7
Warfel, Noel A; Niederst, Matt; Newton, Alexandra C (2011) Disruption of the interface between the pleckstrin homology (PH) and kinase domains of Akt protein is sufficient for hydrophobic motif site phosphorylation in the absence of mTORC2. J Biol Chem 286:39122-9

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