The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth.

Abstract

Phosphoinositide 3‐kinases (PI3Ks) have been identified in an evolutionarily diverse range of organisms, including mammals, Drosophila, yeast, plants and Dictyostelium. They are activated by a multitude of extracellular signals and implicated in mitogenesis, differentiation and cell survival, as well as in the control of the cytoskeleton and cell shape. Here we describe the molecular and functional analysis of Drosophila p110 (Dp110). A full‐length Dp110 cDNA was isolated and found to encode a protein homologous throughout its length to the class I mammalian PI3Ks p110alpha and p110beta. Overexpression of Dp110 in wing or eye imaginal discs resulted in flies with enlarged wings or eyes respectively. In contrast, overexpression of Dp110 containing a mutation predicted to result in the loss of catalytic activity resulted in smaller wings and eyes. The alterations in wing size result from changes in both cell size and cell number, whereas in the eye only differences in cell size were detected. These data imply a role for Dp110 in growth control during Drosophila development and have implications for the function of class I PI3Ks in other organisms.

Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model

“…In this screen, we identified PI3K RNAi and Akt RNAi as strong suppressors of the growth caused by Ras V12 , Dlg RNAi . PI3K and Akt are both components of the PI3K pathway (Leevers et al, 1996;Verdu et al, 1999;Weinkove et al, 1999;Scanga et al, 2000). Knockdown of either gene in an Ras V12 , Dlg RNAi background caused a complete suppression of the neoplastic growth and even caused a near-complete absence of mutant eye cells (Figures 1a-c and m).…”

The conserved PI3′K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila

“…This maternal role for Dakt1 prompted us to test for a potential role for PI3'K signaling in early Drosophila embryos. The ability of a dominant negative mutant of the catalytic subunit of Drosophila PI3'K (Dp110 D954A ) (Leevers et al, 1996) to a ect cell viability in early embyros was therefore tested. Expression of high levels of Dp110 D954 resulted in the extensive loss of cuticle ( Figure 1e) and a high incidence of DNA fragmentation as assayed by TUNEL staining (Figure 1f) indicative of apoptosis.…”

“…To assess this further, the ability of the catalytic subunit of PI3'K (Dp110) to directly activate D-Akt was analysed. For these experiments, cl-8 cell lines expressing wild-type Dp110 (WT Dp110) (Leevers et al, 1996) under the control of an inducible metallothionein (MT-1) promoter were used. Treatment of these cells with CuSO4 resulted in a 3 ± 5-fold increase in WT-Dp110 protein levels ( Loss of Dp110 activity in larval imaginal discs has been shown to result in the decrease of cell size and number (Leevers et al, 1996;Weinkove et al, 1999).…”

“…Recent studies in Drosophila have implicated a role for an insulin-receptor-substrate (IRS) protein (encoded by the chico gene) and phosphatidylinositol-3-OH kinase (PI3'K) in the regulation of cellular growth (BoÈ hni et al, 1999;Leevers et al, 1996;Weinkove et al, 1999). In chico mutants, all aspects of development are normal except for the diminutive size of homozygous chico¯ies (BoÈ hni et al, 1999;Lehner, 1999).…”

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

“…A large amount of evidence supports a pivotal role for the phosphatidylinositol 3‐OH kinase (PI3K)/Akt/mTORC‐1 axis in the establishment of such a crosstalk. Studies showed that mutating several components of this signaling pathway influences both cell size and number, hence affecting organ size (Böhni et al, 1996; Leevers et al, 1996; Goberdhan et al, 1999). Likewise, inactivating mutations of genes leading to deregulated mTORC‐1 activity and failed metabolic checkpoints cause syndromes characterized by multiple, tumor‐like outgrowths in humans, such as Cowden syndrome (Liaw et al, 1997) and tuberous sclerosis (Brook‐Carter et al, 1994).…”