Disease relevance of Pi3K92E

• Our results raise the possibility that neurofibroma formation in individuals with neurofibromatosis might result in part from a Ras-PI3K-Akt-dependent inhibition of FOXO within Schwann cells [1].
• In step mutant animals both cell size and cell number are reduced, resulting in decreased body size and body weight in larvae, pupae and adults. step acts upstream of PI(3)K and is required for the proper regulation of Akt and the transcription factor FOXO [2].
• In contrast to the mild effects of removing HM site phosphorylation at normal levels of PI3K activity, loss of TORC2 activity strongly inhibited hyperplasia caused by elevated pathway activity, as in mutants of the tumor suppressor PTEN [3].
• To begin a genetic analysis of the role of p120 Ras-GAP we identified a homolog from the fruit fly Drosophila melanogaster through its ability to complement the sterility of a Schizosaccharomyces pombe (fission yeast) gap1 mutant strain [4].
• TRB3 expression is remarkably reduced in prostate cancer PC-3 cells after inhibition of PI 3-kinase [5].

High impact information on Pi3K92E

• This involves TSC/TOR signaling in the fat body, and a remote inhibition of organismal growth via local repression of PI3-kinase signaling in peripheral tissues [6].
• Here, we present evidence indicating that Ras(V12) promotes cell growth and G(1)/S progression by increasing dMyc protein levels and activating dPI3K signaling, and that it does so via separate effector pathways [7].
• These results suggest that Ras may only affect PI3K signaling when mutationally activated, such as in Ras(V12)-transformed cells, and provide a basis for understanding the synergy between Ras and other growth-promoting oncogenes in cancer [7].
• We demonstrate that DPTEN modulates tissue mass by acting antagonistically to the Drosophila Class I phosphatidylinositol 3-kinase, Dp110, and its upstream activator Chico, an insulin receptor substrate homolog [8].
• It acts in opposition to Dp110 to control cell number and growth, while coordinately influencing events at the cell periphery via its effects on the actin cytoskeleton [8].

Biological context of Pi3K92E

• The inhibition of Dp110 activity reduces the rate of increase in cell number in the imaginal discs, suggesting that Dp110 normally promotes cell division and/or cell survival [9].
• In addition, modulating Dp110 activity increases or reduces cell size in the developing imaginal disc, and does so throughout the cell cycle [9].
• Unlike direct manipulation of cell-cycle progression, manipulation of Dp110 activity in one compartment of the disc influences the size of that compartment and the size of the disc as a whole [9].
• RESULTS: Null mutations in Dp110 and p60 were generated and used to demonstrate that they are essential genes that are autonomously required for imaginal disc cells to achieve their normal adult size [9].
• In mammalian cells, insulin-induced PI3K (phosphoinositide 3-kinase) activation, generates the lipid second messenger PtdIns(3,4,5) P (3), which is thought to play a key role in triggering the activation of S6K [10].

Anatomical context of Pi3K92E

• We report here the cloning of a novel PI 3-kinase, p170, from cDNA of insulin-sensitive mouse 3T3-L1 adipocytes [11].
• In this study, we show that elevated signaling through PI3K and Akt can prevent developmentally controlled death in the salivary glands of the fruit fly [12].
• The P3k oncoprotein [homolog of the catalytic subunit p110alpha of class 1A phosphoinositide 3-kinase (PI3K)] and its downstream effector Akt induce oncogenic transformation in cultures of chicken embryo fibroblasts (CEF) [13].
• Furthermore, co-purification of the catalytic subunit of PI3K (p110) was achieved from lysates of co-transfected S2 cells as well as RBL-2H3 mast cells stably expressing isc-p85alpha [14].
• Together, these data suggest that p120 is an important positive modulator of adhesion but that it is not an essential core component of adherens junctions [15].

Associations of Pi3K92E with chemical compounds

• The insulin-induced activations of dERK and dAKT were blocked by LY294002, dPTEN, and by an AKT inhibitor, indicating involvement of dPI3K and dAKT in the insulin-induced dERK and dAKT activations [16].
• Thus, Dp110 integrates inputs from its phosphotyrosine-binding adaptor and Ras to achieve maximal PI(3)K signalling in specific biological situations [17].
• PI3K inhibitors or the proteasome inhibitor lactacystin interfere with this process [13].
• We also observed impairment of PI3K/Akt signaling in the fly parkin model of PD, hinting at a common molecular event in the pathogenesis of PD [18].
• Sequence analysis suggests that HsC2-PI3K is a second distinct mammalian member of the C2 domain-containing PI 3-kinase family [19].

Other interactions of Pi3K92E

• Our results indicate that Dp110 and p60 signalling can affect growth in multiple ways, which has important implications for the function of signalling through class I(A) PI 3-kinases [9].
• Studies in Drosophila have identified an evolutionarily conserved signaling pathway that regulates organismal size and that includes the Drosophila insulin receptor substrate homolog Chico, the lipid kinase PI(3)K (Dp110), DAkt1/dPKB, and dS6K [20].

Analytical, diagnostic and therapeutic context of Pi3K92E

• CONCLUSIONS: We conclude that during imaginal disc development, Dp110 and p60 regulate cell size, cell number and organ size [9].
• In contrast, expression of either dominant-negative (dn) Ras, Raf, or PI3K increases body size and prolongs the larval stages, leading to delayed pupariation, whereas expression of dn-PI3K, but not of dn-Raf or dn-Ras, reduces PG cell size [21].
• We used the reversible phosphoinositide-3 kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one [LY294002 (LY)] and we examined its effects by intracellular recording, fluorescence imaging with styryl dyes (FM 1-43 and FM 2-10), calcium imaging, and electron microscopy [22].

References