Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity

PTEN, a tumor suppressor among the most commonly mutated proteins in human cancer, is recognized to be both a protein phosphatase and a phosphatidylin ositol 3,4,5-trisphosphate (PtdIns(3,4,5)P-3) 3-phosphatase. Previous work [Maehama and Dixon, J. Biol, Chem. 273 (1998) 13375-13378] has led to a con sensus that inositol phosphates are not physiologically relevant substrates for PTEN. In contrast, ne demonstrate that PTEN is an active inositol 1,3, 4,5,6-penta-kisphosphate (Ins(1,3,4,5,6)P-5) 3-phosphatase when expressed a nd purified from bacteria or HEK cells, Kinetic data indicate Ins(1,3,3,5,6 )P-5 (K-m = 7.1 muM) and PtdIns(3,4,5)P-3 (K-m = 26 muM) compete for PTEN i n vivo. Transient transfection of HEK cells with PTEN decreased Ins(1,3,4,5 ,6)Ps levels. We discuss the physiological significance of these studies in relation to recent work showing that dephosphorylation of Ins(1,3,4,5,6)P- 5 to inositol 1,4,5,6-tetrakisphosphate is a cell signaling event. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Scienc e B.V. All rights reserved.