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General Information
Name
cancer, multiple, PI3K-AKT signaling pathway
FlyBase ID
FBhh0000400
Disease Ontology Term
Parent Disease
OMIM
Overview

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) and Pten (ortholog of human PTEN phosphatase, a negative regulator of the PI3K/AKT pathway). Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both Pten and Pi3K92E. Other Drosophila genes in this pathway include Pdk1 (ortholog of human PDPK1 kinase) and Akt1 (orthologous to human AKT kinase genes).

Dmel\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 OMIM:601728). UAS constructs of the human Hsap\PTEN gene have been introduced into flies; heterologous rescue has not been tested.

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.

Many physical and genetic interactions of Dmel\Pten have been described; see below and in the Pten gene report. See also Vinayagam et al., 2016 (FBrf0233454), which describes a comprehensive analysis of the InR/PI3K/AKT network in Drosophila.

[updated Dec. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, multiple, PI3K-AKT signaling pathway
OMIM report
Human gene(s) implicated
Symptoms and phenotype
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]
Genetics
PIK3CA has been implicated in multiple cancers and in inherited disorders with increased risk of developing cancer. [from OMIM:171834; 2016.09.30]
Cellular phenotype and pathology
Molecular information
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 OMIM:601728, 2017.11.24]
External links
Disease synonyms
PI3K-PKB/AKT pathway
PI3K-AKT-mTOR pathway
PTEN-PI3K-AKT signaling
PI3 kinase-AKT
Search term: insulin-PI3K signaling
cancer, multiple, PIK3C-related
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
One to one: 1 human to 1 Drosophila.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    Pi3K92E (Pi3K92E) encodes the catalytic subunit of a class I phosphatidylinositol 3-kinase that functions downstream of the product of InR and other receptors during several processes, including cell and tissue growth. [Date last reviewed: 2018-09-13]
    Gene Groups / Pathways
    Comments on ortholog(s)
    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.
    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Gene Snapshot
    Phosphatase and tensin homolog (Pten) encodes a dual lipid and protein phosphatase that primarily counters the effects of the insulin-regulated lipid kinase, encoded by Pi3K92E. It inhibits cell growth, cell proliferation and cellular events controlling cytoskeletal and junctional rearrangements. [Date last reviewed: 2018-10-18]
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)
    High-scoring ortholog of human PTEN (1 Drosophila to 1 human). Dmel\Pten shares 41% identity and 57% similarity with the human gene.
    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (124 groups)
    protein-protein
    Interacting group
    Assay
    References
    protein kinase assay, autoradiography
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, peptide massfingerprinting, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry, peptide massfingerprinting
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry, peptide massfingerprinting, western blot, anti bait coimmunoprecipitation, protein kinase assay, autoradiography, pull down, anti tag western blot
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, peptide massfingerprinting, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    two hybrid, pull down, western blot
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot, two hybrid
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)
    Models Based on Experimental Evidence ( 4 )
    Modifiers Based on Experimental Evidence ( 4 )
    Models Based on Experimental Evidence ( 1 )
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    References (10)