| 19325558 |
Ivetac I, Gurung R, Hakim S, Horan KA, Sheffield DA, Binge LC, Majerus PW, Tiganis T, Mitchell CA: Regulation of PI (3) K/Akt signalling and cellular transformation by inositol polyphosphate 4-phosphatase-1. EMBO Rep. 2009 May;10(5):487-93. Epub 2009 Mar 27.
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. |
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