Naslov
Regulation of PI(3)K/Akt signalling and cellular transformation by inositol polyphosphate 4‐phosphatase‐1

Autori
Ivetac, Ivan ; Gurung, Rajendra ; Hakim, Sandra ; Horan, Kristy A ; Sheffield, David A ; Binge, Lauren C ; Majerus, Philip W ; Tiganis, Tony ; Mitchell, Christina A

Izvornik
EMBO reports (1469-221X) 10 (2009), 5; 487-493

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Phosphoinositides ; PI(3)-kinase ; Akt ; 4-phosphatase ; cell signaling ; proliferation ; cell survival ; apoptosis ; oncogenesis

Sažetak
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)P3 and PtdIns(3, 4)P2, direct Akt plasma membrane engagement. Pathological Akt plasma membrane association promotes oncogenesis. PtdIns(3, 4)P2 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 Ser473 and Thr308-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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Interdisciplinarne prirodne znanosti, Temeljne medicinske znanosti

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