Naslov
The multifunctional role of the type I inositol polyphosphate 4-phosphatase in the cellular signalling and trafficking pathways

Autori
Ivetac, Ivan.

Vrsta, podvrsta i kategorija rada
Ocjenski radovi, doktorska disertacija

Fakultet
Faculty of Medicine, Dept. of Biochemistry and Molecular Biology, Monash University.

Mjesto
Melbourne (Clayton), Victoria, Australia

Datum
12.05

Godina
2007

Stranica
299

Mentor
Mitchell, Christina Anne

Neposredni voditelj
Ooms, Lisa

Ključne riječi
Cellular signal transduction ; Intracellular trafficking ; 4-phosphatase ; Phosphatidylinositol-3, 4-bisphosphate ; Phosphatidylinositol-3-kinases ; PI 3-kinases

Sažetak
The type I 4-phosphatase localizes to endosomal membranes, generating PtdIns(3)P via hydrolysis of PtdIns(3, 4)P2, thereby rescuing the phenotype of wortmannin-induced endosomal dilatation. After epidermal growth factor (EGF) stimulation, the 4-phosphatase translocates to the PM and inhibits the PM recruitment of the TAPP1 PH domain. The 4-phosphatase contains an N-terminal tandem C2 domain that is essential for catalytic activity, endosomal localization, and regulation of the recruitment of effectors with PtdIns(3, 4)P2-specific PH domains to the PM. The 4-phosphatase hence functions in both generating PtdIns(3)P on endosomal membranes and terminating PtdIns(3, 4)P2 signals at the PM. 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, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

POVEZANOST RADA