New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway

Abstract

The most recently discovered PTEN tumor suppressor gene has been found to be defective in a large number of human cancers. In addition, germ-line mutations in PTEN result in the dominantly inherited disease Cowden syndrome, which is characterized by multiple hamartomas and a high proclivity for developing cancer. A series of publications over the past year now suggest a mechanism by which PTEN loss of function results in tumors. PTEN appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell growth and survival by dephosphorylating the 3 position of phosphoinositides.

Figure 1

Reactions catalyzed by PI3K and PTEN. (A) PtdIns contains a myo-inositol headgroup connected to diacylglycerol by a phosphodiester linkage. The numbering system of the inositol ring is indicated. (B) The class I PI3K enzymes can phosphorylate the 3 position of PtdIns, PtdIns-4-P, or PtdIns-4,5-P₂ to produce PtdIns-3-P, PtdIns-3,4-P₂, or PtdIns-3,4,5-P₃, respectively. PtdIns-3,4-P₂ can also be produced by dephosphorylating the 5 position of PtdIns-3,4,5-P₃, and one enzyme that does this is an SH2-containing 5-phosphatase called SHIP. In addition, PtdIns-3,4-P₂ can be produced by phosphorylating the 4 position of PtdIns-3-P [reviewed by Fruman et al. (76)]. PTEN has been shown to dephosphorylate the 3 position of both PtdIns-3,4,5-P₃ (26, 43) and PtdIns-3,4-P₂ (44) to reverse the reactions catalyzed by PI3K.

Figure 2

Cell survival and proliferation by means of PI3K and AKT and suppression by PTEN. Growth factors and survival factors activate receptors that recruit PI3K to the membrane. Phosphorylation of the membrane lipids PtdIns-4-P and PtdIns-4,5-P₂ [PI4P, PI4,5P₂] by PI3K produces the second messengers PtdIns-3,4-P₂ and PtdIns-3,4,5-P₃ [PI3,4P₂, PI3,4,5P₃]. These lipids recruit the protein-serine/threonine kinases AKT and PDK1 to the membrane and induce a conformational change in AKT, exposing the activation loop. Phosphorylation of AKT at Thr-308 of the activation loop by PDK1 turns on the protein kinase activity. Phosphorylation of AKT at a C-terminal site (not shown) causes further activation. AKT phosphorylates and compromises the function of BAD and caspase-9, proteins involved in cell death pathways. AKT also phosphorylates and inhibits glycogen synthase kinase 3 (GSK3). GSK3 phosphorylates cyclin D, targeting it for proteolysis; thus, AKT may promote cyclin D accumulation. PDK1 also phosphorylates and enables activation of p70^S6kinase and protein kinase C (PKC) family members. PTEN turns off the pathway by dephosphorylating the 3 position of PtdIns-3,4-P₂ and PtdIns-3,4,5-P₃.