title: Regulation of PI(3)K/Akt signalling and cellular transformation by inositol polyphosphate 4-phosphatase-1.
abstract: Akt is a crucial phosphoinositide 3-kinase (PI(3)K) effector that regulates cell proliferation and survival. PI(3)K-generated signals, PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2), direct Akt plasma membrane engagement. Pathological Akt plasma membrane association promotes oncogenesis. PtdIns(3,4)P(2) is degraded by inositol polyphosphate 4-phosphatase-1 (4-ptase-1) forming PtdIns(3)P; however, the role of 4-ptase-1 in regulating the activation and function of Akt is unclear. In mouse embryonic fibroblasts lacking 4-ptase-1 ((-/-)MEFs), the Akt-pleckstrin homology (PH) domain was constitutively membrane-associated both in serum-starved and agonist-stimulated cells, in contrast to (+/+)MEFs, in which it was detected only at the plasma membrane following serum stimulation. Epidermal growth factor (EGF) stimulation resulted in increased Ser(473) and Thr(308)-Akt phosphorylation and activation of Akt-dependent signalling in (-/-)MEFs, relative to (+/+)MEFs. Significantly, loss of 4-ptase-1 resulted in increased cell proliferation and decreased apoptosis. SV40-transformed (-/-)MEFs showed increased anchorage-independent cell growth and formed tumours in nude mice. This study provides the first evidence, to our knowledge, that 4-ptase-1 controls the activation of Akt and thereby cell proliferation, survival and tumorigenesis.
authors.affiliation: Department of Biochemistry, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ivetac
authors.forename: Rajendra
authors.initials: R
authors.lastname: Gurung
authors.forename: Sandra
authors.initials: S
authors.lastname: Hakim
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Horan
authors.forename: David A
authors.initials: DA
authors.lastname: Sheffield
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Binge
authors.forename: Philip W
authors.initials: PW
authors.lastname: Majerus
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell