Disease relevance of Akt1

• 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 [1].
• It was reported that Akt, an essential component of the insulin pathway, stimulates growth by phosphorylating and inhibiting tuberous sclerosis complex 2 (TSC2) [2].
• PKB/AKT was identified from an oncogene, v-akt, found in a rodent T-cell lymphoma [9] [3].
• 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 [4].

High impact information on Akt1

• A mutant form of AKT lacking the HM phosphorylation site displayed comparable activity [5].
• Growth inhibition is associated with a reduction in S6K but not PKB/Akt activity [6].
• Together, genetic and biochemical analysis places Scylla/Charybdis downstream of PKB and upstream of TSC [6].
• Tsc2 is not a critical target of Akt during normal Drosophila development [2].
• The direct mechanism by which the serine/threonine kinase Akt (also known as protein kinase B (PKB)) regulates cell growth is unknown [7].

Biological context of Akt1

• BACKGROUND: The activation of protein kinase B (PKB, also known as c-Akt) is stimulated by insulin or growth factors and results from its phosphorylation at Thr308 and Ser473 [8].
• Dakt1 was mapped to Drosophila chromosome 3R 89BC [9].
• The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies in the genome of vertebrate and invertebrate eucaryotes. Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1 [9].
• The Akt proto-oncogene encodes a serine-threonine protein kinase whose carboxyterminal catalytic domain is closely related to the catalytic domains of all the known members of the protein kinase C (PKC) family [9].
• This in turn finely tunes activation of Akt1, a process essential for proper morphogenesis of the light-gathering organelle, consisting of a stack of F-actin rich microvilli within the apical membrane [10].

Anatomical context of Akt1

• 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) [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].
• Phosphatidylinositol 3-kinase and Akt nonautonomously promote perineurial glial growth in Drosophila peripheral nerves [4].
• Akt directly stimulates the activity of translation initiation factors and upregulates ribosome biogenesis [13].
• In vivo activation of PKB/AKT necessitates its recruitment to the cell membrane mediated by the N-terminal pleckstrin homology (PH) domain [14].

Associations of Akt1 with chemical compounds

• Akt, however, differs from PKC in its N-terminal region which contains a domain related distantly to the SH2 domain of cytoplasmic tyrosine kinases and other signalling proteins, which we have named Akt homology (AH) domain [9].
• Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B [15].
• Here we show that genetic manipulation of the phosphoinositide-3-OH-kinase-dependent serine/threonine protein kinase Akt (protein kinase B) during development of the Drosophila imaginal disc affects cell and organ size in an autonomous manner [16].
• 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 [17].
• 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].
• We conclude that isoforms of PP2A-B' can act as subcellular-compartment-specific regulators of PI3-kinase/PTEN/Akt kinase signalling and IIS, potentially providing new targets for modulating individual subcellular pools of activated Akt in insulin-linked disease [19].

Regulatory relationships of Akt1

• PDK1 regulates growth through Akt and S6K in Drosophila [20].
• Akt is regulated by phosphatidylinositol 3-OH kinase (PI3'K) signaling and has shown to be hyperactivated through the loss of the PTEN tumor suppressor [21].
• FOXO activity is inhibited by the insulin effector kinase Akt; we show that Akt activation is systemically reduced as a result of M. marinum infection [22].

Other interactions of Akt1

• This functional interaction between dPDK-1 and Dakt1 was further confirmed through genetic analyses in Drosophila [23].
• The conserved PI3'K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila [21].
• We also show that Drosophila AKT (DAKT) activation depends on the insulin receptor substrate, CHICO (IRS1-4) [24].
• Epistasis experiments and a variety of biochemical studies that followed have indicated a critical function for these proteins in the highly conserved PI-3-kinase-Akt-mTOR signalling pathway [25].
• Applying a combined genetic and biochemical approach has led to the identification of a new protein kinase B/Akt target, the transcription factor Trachealess [26].

Analytical, diagnostic and therapeutic context of Akt1

• Although genetic analysis in Caenorhabditis elegans has implicated Akt as the only relevant PDK1 substrate, cell culture studies have suggested that PDK1 has additional targets [20].
• One of them was cloned, and found by sequence analysis, to define an Akt related gene (Dakt1) [9].
• RESULTS: Cycle sequencing of the purified PCR products did not reveal any mutation of the PH domain of PKB/AKT [14].

References