The complexity of PTEN: mutation, marker and potential target for therapeutic intervention.
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.
Steelman
Linda S
LS
East Carolina University, Department of Microbiology and Immunology, Brody School of Medicine, Brody Building 5N98C, Greenville, NC 27834, USA.
Bertrand
Fred E
FE
McCubrey
James A
JA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000201:enzymology; D005260:Female; D016147:Genes, Tumor Suppressor; D006223:Hamartoma Syndrome, Multiple / Q000201:enzymology; D006801:Humans; D008171:Lung Diseases / Q000201:enzymology; D008297:Male; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051059:PTEN Phosphohydrolase; D018129:Phosphatidylinositol Phosphates / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D018129:Phosphatidylinositol Phosphates; D010743:Phospholipids; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus