Jr. Halstead et al., A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress, CURR BIOL, 11(6), 2001, pp. 386-395
Background: Phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P-3] is
a key second messenger found ubiquitously in higher eukaryotic cells. The a
ctivation of Class I phosphoinositide 3-kinases and the subsequent producti
on of PtdIns(3,4,5)P-3 is an important cell signaling event that has been c
ausally linked to the activation of a variety of downstream cellular proces
ses, such as cell migration and proliferation. Although numerous proteins r
egulating a variety of biological pathways have been shown to bind PtdIns(3
,4,5)P-3, there are no data to demonstrate multiple mechanisms for PtdIns(3
,4,5)P-3 synthesis in vivo.
Results: In this study, we demonstrate an alternative pathway for the in vi
vo production of PtdIns(3,4,5)P-3 mediated by the action of murine Type I a
lpha phosphatidylinositol 4-phosphate 5-kinase (Type I alpha. PIPkinase), a
n enzyme best characterized as regulating cellular PtdIns(4,5)P-2 levels. A
nalysis of this novel pathway of PtdIns(3,4,5)P-3 synthesis in cellular mem
branes leads us to conclude that in vivo, Type I alpha PiPkinase also acts
as a PtdIns(3,4)P-2 5-kinase. We demonstrate for the first time that cells
actually contain an endogenous PtdIns(3,4)P-2 5-kinase, and that during oxi
dative stress, this enzyme is responsible for PtdIns(3,4,5)P, synthesis. Fu
rthermore, we demonstrate that by upregulating the H2O2-induced PtdIns(3,4,
5)P-3 levels using overexpression studies, the endogenous PtdIns(3,4)P-2 5-
kinase is likely to be Type I alpha PIPkinase.
Conclusions: We describe for the first time a novel in vivo activity for Ty
pe tcr PIPkinase, and a novel pathway for the in vivo synthesis of function
al PtdIns(3,4,5)P-3, a key lipid second messenger regulating a number of di
verse cellular processes.