Inhibiting PTEN.
PTEN (phosphatase and tensin homologue deleted on chromosome 10) is well known as a tumour suppressor. In dephosphorylating the 3-position of the inositol ring of phosphoinositides such as PtdIns(3,4,5)P(3), PTEN's lipid phosphatase activity is an important counteracting mechanism in PI3K (phosphoinositide 3-kinase) signalling. This is essential for cell motility and migration due to the achievement of a PtdIns(3,4,5)P(3)/PtdIns(4,5)P(2) gradient that is also involved in metastasis. Furthermore, PTEN's tumour suppressor role is linked to the control of cell-cycle progression and cell proliferation by counteracting Akt (also called protein kinase B) signalling which is PtdIns(3,4,5)P(3)-dependent. Akt is upstream of several kinases involved in proliferation and apoptotic signalling which are often found to be deregulated or mutated in tumours. However, Akt is also the key enzyme in insulin signalling regulating glucose uptake and cell growth. Therefore PTEN has recently moved into the spotlight as a drug target in diabetes. This review summarizes studies undertaken on PTEN's role in glucose uptake, insulin resistance, diabetes and its controversial role in GLUT (glucose transporter)-mediated glucose uptake. Currently available techniques for inhibiting PTEN and the suitability of PTEN as a drug target will be discussed.
Rosivatz
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Division of Cell and Molecular Biology, Imperial College London, Exhibition Road, London, UK. e.rosivatz@ic.ac.uk
D002879:Chromosomes, Human, Pair 10; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics
D004791:Enzyme Inhibitors; D007328:Insulin; D051059:PTEN Phosphohydrolase; D005947:Glucose