A number of Drosophila genes within the PI3K-AKT signaling pathway have been used in models of cancer, including Pi3K92E (orthologous to human PIK3C kinase catalytic subunit genes), Pten (ortholog of human PTEN phosphatase, a negative regulator of the PI3K/AKT pathway), and Akt (orthologous to human AKT kinase genes). Other Drosophila genes in this pathway include Pdk1 (ortholog of human PDPK1 kinase). See the FlyBase pathway report 'Insulin-like Receptor Signaling Pathway' (FBgg0000910). See, also, the human disease model 'cancer, multiple, NOTCH-PI3K-AKT-related' (FBhh0000937).
A constitutively activate form of Dmel\Pi3K92E has been used in a model of lung cancer, using tracheal-specific GAL4 drivers. Overexpression of Dmel\Akt in the tracheal system has also been used in a model of lung cancer. Pi3K92E has been used in a Drosophila model of glioma in combination with EGFR, see 'cancer, malignant glioma, EGFR-PIK3C-related' (FBhh0000401).
The human PTEN gene has been identified as a tumor suppressor that is mutated in a large number of cancers, especially in advanced stages (see MIM:601728). UAS constructs of the human Hsap\PTEN gene have been introduced into flies; heterologous rescue (functional complementation) has been demonstrated for the overgrowth phenotype of hypomorphic mutations of Dmel\Pten. Recently, a large number of mutations analogous to variants implicated in human disease have been introduced as transgenic Hsap\PTEN constructs. See the 'Disease-Implicated Variants' table, below, for tested variants associated with PTEN-related cancers. See the Hsap\PTEN gene report for a complete list of tested variants.
Animals homozygous for loss-of-function alleles of Dmel\Pten die during the larval stage. When induced in larvae, clones of cells carrying an amorphic mutation of Pten exhibit mild hypertrophic growth, with increased cell size but no (or little) increase in cell number. However, under conditions of nutrient restriction, cells in clones lacking Pten switch from hypertrophic growth to hyperplastic growth. This hyperproliferation occurs at the expense of neighboring wild-type cells. Under the nutrient restriction conditions, induction of insulin signaling in the surrounding cells suppresses the overgrowth of Pten mutant clones. Thus, this works may reflect an integration of PTEN roles as a tumor suppressor and as a negative regulator of insulin-PI3K signaling.
There are over 100 missense and nonsense mutations of human PTEN implicated in several different diseases. As part of a large-scale assessment of such variants an assay in Drosophila was employed. Ubiquitous expression of wild-type Hsap\PTEN results in delayed eclosion; expression of a complete loss-of-function variant of Hsap\PTEN does not. This allows an assessment of degree of wild-type function for PTEN variants found in human; 86 variants have been assessed in this assay.
[updated Apr.2024 by FlyBase; FBrf0222196]
The PI3K-AKT signalling pathway, which controls multiple cellular processes including metabolism, motility, proliferation, growth, and survival, is one of the most frequently dysregulated pathways in human cancers. (Recent reviews: Janku et al., 2018, pubmed:29508857; Manning and Toker, 2017, pubmed:28431241.)
PTEN has been identified as a tumor suppressor that is mutated in a large number of cancers at high frequency; it functions as a tumor suppressor by negatively regulating the PI3K-AKT signaling pathway. [Gene Cards, PTEN; 2018.12.10]
PIK3CA has been implicated in multiple cancers and in inherited disorders with increased risk of developing cancer. [from MIM:171834; 2016.09.30]
PIK3 (Phosphatidylinositol 3-kinase) activates signaling cascades involved in cell growth, survival, proliferation, motility and morphology. "PIK3C" refers to the catalytic subunit with kinase activity. Multiple genes encode different catalytic subunits and at least two genes encode regulatory subunits. One of the genes encoding a catalytic subunit, PIK3CA (Phosphatidylinositol 3-kinase catalytic subunit alpha), has been implicated in cancer. [from Gene Cards, PIK3CA; 2016.09.30]
PI3-kinase and PTEN are major positive and negative regulators, respectively, of the PI3-kinase pathway, which regulates growth, survival, and proliferation. These key signaling components are two of the most frequently mutated proteins in human cancers, resulting in unregulated activation of PI3K signaling. (Chalhoub and Baker, 2009; pubmed:18767981)
PTEN encodes a protein that acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins; it also acts as a lipid phosphatase. The lipid phosphatase activity may be critical for its tumor suppressor function. [Gene Cards, PTEN; 2018.12.10]
PTEN acts as a negative regulator of insulin-PI3K signaling (Gupta and Dey, 2012; pubmed:22875989).
The PTEN gene encodes a ubiquitously expressed tumor suppressor dual-specificity phosphatase that antagonizes the PI3K signaling pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (summary by Pezzolesi et al., 2007; pubmed:17341483). [from MIM:601728, 2017.11.24]
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human PIK3CD and PIK3CB; moderate-scoring ortholog of PIK3CG and PIK3CA (1 Drosophila to 4 human). Dmel\Pi3K92E shares 31-39% identity and 50-58% simiilarity with the human genes.
High-scoring ortholog of human PTEN (1 Drosophila to 1 human). Dmel\Pten shares 41% identity and 57% similarity with the human gene.
Moderate- to high-scoring ortholog of human genes AKT2, AKT3, and AKT1 (1 Drosophila to 3 human). Dmel\Akt shares 60-64% identity and 75-77% similarity with these human genes.
