The complexity of PTEN: mutation, marker and potential target for therapeutic intervention

• Published in: Expert opinion on therapeutic targets Vol. 8; no. 6; p. 537
• Main Authors: Steelman, Linda S, Bertrand, Fred E, McCubrey, James A
• Format: Journal Article
• Language: English
• Published: England 01.12.2004
• Subjects: Animals; Apoptosis - physiology; Biomarkers, Tumor - physiology; Cell Cycle - physiology; Cell Nucleus - enzymology; Female; Genes, Tumor Suppressor; Hamartoma Syndrome, Multiple - enzymology; Humans; Lung Diseases - enzymology; Male; Mice; Models, Biological; Neoplasm Proteins - physiology; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Phosphatidylinositol Phosphates - physiology; Phospholipids - metabolism; Phosphoproteins - metabolism; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - physiology; Phosphorylation; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein-Tyrosine Kinases - physiology; PTEN Phosphohydrolase; Receptor, Insulin - physiology; Signal Transduction - genetics; Signal Transduction - physiology; Sirolimus - pharmacology; Sirolimus - therapeutic use; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - physiology
• ISSN: 1744-7631
• DOI: 10.1517/14728222.8.6.537

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a phosphatase that removes phosphates primarily from lipids. It has also been called mutated in multiple advanced cancers 1 and transforming growth factor-beta regulated epithelial cell-enriched phosphatase 1. The best described substrate of PTEN is phosphatidyliniositol (3,4,5)-tris-phosphate [PtdIns(3,4,5)P3]. PTEN removes the phosphate in PtdIns(3,4,5)P(3) to generate PtdIns(4,5)P(2). PTEN serves to counter-balance the effects of phosphoinositide 3' kinase, which normally adds a phosphate to PtdIns(4,5)P(2) to generate PtdIns(3,4,5)P(3). PtdIns(3,4,5)P(3) recruits kinases such as phosphoinositide-dependent kinase 1, which in turn phosphorylate Akt, which phosphorylates other downstream proteins involved in regulation of apoptosis and cell-cycle progression. PTEN removal of the phosphate from PtdIns(3,4,5)P(3) inhibits this pathway by preventing localisation of proteins with pleckstrin homology domains to the cell membrane. Alterations of the PTEN gene are associated with cancer and other diseases. Novel therapeutic approaches have been developed to counteract the deletion/mutation of PTEN in human cancer. This review will discuss the role of PTEN in signal transduction and cancer as well as pharmacological approaches to combat PTEN loss in human cancer.