PTEN targeting: the search for novel insulin sensitisers provides new insight into obesity research

Abstract

phosphatidylinositol 3,4,5-trisphosphatePTEN phosphatase and tensin homologueSH2 SRC homology domain 2SHIP SH2-containing inositol 5-phosphataseBreakthrough information in one field of science is oftengenerated by studies in other areas. This has been the casefor the phosphatase and tensin homologue (PTEN) and itsidentification as a drug discovery target for type 2 diabetes.In 1996, the susceptibility gene for Cowden syndrome (nowknown as PTEN) was mapped to human chromosome10q22–q23 [1]. Cowden syndrome is an autosomaldominant disorder characterised by multiple hamartomas,which affect derivatives of all three germ layers, andincreased risks of breast, thyroid and endometrial cancers[2]. Germline mutations in the tumour-suppressor genePTEN have been found in 80% of patients affected byCowden syndrome [3]. PTEN encodes a dual-function lipidand protein phosphatase that represents a major 3-phospha-tase in the phosphatidylinositol 3-kinase (PI3K)/Akt sig-nalling system [4, 5]. PTEN also represents the firstphosphatase gene to be implicated in the aetiology of aninherited cancer syndrome. A number of disorders associ-ated with germline PTEN mutations have been subsequent-ly recognised.Following insulin exposure, the PI3K-dependent in-crease in levels of phosphatidylinositol 3,4,5-trisphosphate(PIP