Turning off AKT: PHLPP as a drug target

Newton, A. C., Trotman, L. C. (2014) Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol, 54. pp. 537-58. ISSN 1545-4304 (Electronic)0362-1642 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/24392697
DOI: 10.1146/annurev-pharmtox-011112-140338

Abstract

Precise control of the balance between protein phosphorylation, catalyzed by protein kinases, and protein dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Dysregulation of this balance leads to pathophysiological states, driving diseases such as cancer, heart disease, and diabetes. Aberrant phosphorylation of components of the pathways that control cell growth and cell survival are particularly prevalent in cancer. One of the most studied tumor suppressors in these pathways is the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten), which dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), thus preventing activation of the oncogenic kinase AKT (v-akt murine thymoma viral oncogene homolog). In 2005, the discovery of a family of protein phosphatases whose members directly dephosphorylate and inactivate AKT introduced a new negative regulator of the phosphoinositide 3-kinase (PI3K) oncogenic pathway. Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) isozymes comprise a novel tumor suppressor family whose two members, PHLPP1 and PHLPP2, are deleted as frequently as PTEN in cancers such as those of the prostate. PHLPP is thus a novel therapeutic target to suppress oncogenic pathways and is a potential candidate biomarker to stratify patients for the appropriate targeted therapeutics. This review discusses the role of PHLPP in terminating AKT signaling and how pharmacological intervention would impact this pathway.

Item Type: Paper
Uncontrolled Keywords: DNA Primers Gene Expression Regulation Humans Male Molecular Targeted Therapy Nuclear Proteins/genetics/ metabolism Phosphoprotein Phosphatases/genetics/ metabolism Phosphorylation Prostatic Neoplasms/genetics/therapy Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/ metabolism Signal Transduction
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > phosphoinositide 3-kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation
CSHL Authors:
Communities: CSHL labs > Trotman lab
Depositing User: Matt Covey
Date: 2014
Date Deposited: 22 Jul 2015 20:37
Last Modified: 22 Jul 2015 20:37
PMCID: PMC4082184
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31638

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