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Turning off AKT: PHLPP as a drug target
Alexandra C Newton1, Lloyd C Trotman
1Department of Pharmacology, University of California, San Diego, La Jolla, California 92093;
Annual Review of Pharmacology and Toxicology
|January 8, 2014
Summary
Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) directly inactivates the AKT oncogenic pathway, acting as a crucial tumor suppressor. PHLPP offers a novel therapeutic target for cancer treatment and patient stratification.
Area of Science:
- Cellular Biology
- Oncology
- Biochemistry
Background:
- Cellular homeostasis relies on the balance between protein phosphorylation and dephosphorylation.
- Dysregulation of this balance contributes to diseases like cancer, heart disease, and diabetes.
- The tumor suppressor PTEN dephosphorylates PIP3, inhibiting the AKT pathway, but other regulators exist.
Purpose of the Study:
- To review the role of Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) in regulating the AKT signaling pathway.
- To explore PHLPP as a novel therapeutic target and biomarker in cancer.
Main Methods:
- Literature review focusing on PHLPP's function in AKT signaling.
- Analysis of PHLPP's role as a tumor suppressor.
- Discussion of potential pharmacological interventions targeting PHLPP.
Main Results:
- PHLPP isozymes (PHLPP1 and PHLPP2) directly dephosphorylate and inactivate AKT.
- PHLPP acts as a novel tumor suppressor, similar to PTEN, and is frequently deleted in cancers.
- PHLPP represents a new negative regulator of the PI3K/AKT oncogenic pathway.
Conclusions:
- PHLPP is a critical negative regulator of AKT signaling and a promising tumor suppressor.
- PHLPP is a potential therapeutic target for suppressing oncogenic pathways.
- PHLPP may serve as a biomarker for stratifying cancer patients for targeted therapies.
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