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| PI3K/Akt | |
|---|---|
| Name | PI3K/Akt pathway |
| Caption | Schematic representation of PI3K and Akt signaling |
| Organisms | Eukaryotes |
PI3K/Akt
The PI3K/Akt cascade is a central intracellular signaling axis that transduces extracellular cues into cellular responses. It links receptors such as Epidermal growth factor receptor and Insulin receptor to downstream effectors controlling growth, survival, metabolism, and motility. Discovered through studies involving James Watson, Stanley Cohen, and later work in laboratories at Harvard University and Stanford University, the pathway has become a major focus in research by organizations including the National Institutes of Health and the Wellcome Trust.
The pathway originates when receptor tyrosine kinases like Platelet-derived growth factor receptor or G protein–coupled receptors exemplified by β-adrenergic receptor engage ligands such as Epidermal growth factor or Insulin. Adaptor proteins including Grb2 and scaffold proteins like IRS1 recruit class I phosphoinositide 3-kinases typified by catalytic subunits discovered in studies from Cold Spring Harbor Laboratory and Max Planck Society. Generated phosphoinositide lipids serve as docking sites for AGC kinases similar to those characterized in work at University of Cambridge and Massachusetts Institute of Technology, enabling activation of serine/threonine kinase Akt. Downstream targets include effectors studied in contexts like mTOR signaling research at Cancer Research UK and apoptosis regulators examined by investigators at Dana-Farber Cancer Institute.
Class I PI3Ks consist of regulatory and catalytic subunits; catalytic isoforms identified include p110α, p110β, p110γ, and p110δ, with p110α mutations reported in screens at The Sanger Institute and Broad Institute. Akt exists as three isoforms—Akt1, Akt2, Akt3—whose gene loci were mapped in projects supported by the Human Genome Project and annotations from Ensembl. Structural studies using cryo-EM and X-ray crystallography by groups at European Molecular Biology Laboratory and California Institute of Technology revealed domains homologous to PH domains first noted in research involving Walter Gilbert and Frederick Sanger. Isoform-specific roles were delineated in animal models developed at Johns Hopkins University and University of Oxford.
Ligand-induced receptor activation studied in laboratories at Roche and Pfizer recruits PI3K via SH2-containing adaptors such as p85α; p85–p110 complexes generate PIP3 from PIP2 at the plasma membrane, a mechanism explored in foundational work at Yale University and Columbia University. PIP3 accumulation allows PH-domain-containing proteins like Akt and PDK1 to colocalize; PDK1 phosphorylates Akt at threonine residues while mTORC2 phosphorylates a serine residue, processes dissected by teams at University of California, San Francisco and Scripps Research. Activated Akt phosphorylates substrates including GSK3B, FOXO1, and BAD, integrating signals characterized in studies at University of Pennsylvania and Karolinska Institutet.
Akt signaling regulates cell proliferation in models used by Memorial Sloan Kettering Cancer Center and influences metabolism exemplified by insulin-regulated glucose uptake studied at Imperial College London. It controls protein synthesis through effectors like mTOR and TSC2, processes interrogated by researchers at Rockefeller University and Weizmann Institute of Science. The pathway modulates apoptosis pathways investigated in work by Howard Hughes Medical Institute scientists and contributes to cell migration and invasion described in clinical studies at Mayo Clinic and Cleveland Clinic. Developmental roles were highlighted in genetic screens at National Human Genome Research Institute and embryology labs at University of Cambridge.
Negative regulators include lipid phosphatases such as PTEN and protein phosphatases like PP2A, genes and proteins characterized at institutions including Cold Spring Harbor Laboratory and Max Delbrück Center. Crosstalk occurs with MAPK cascade components like RAS and RAF, interactions explored in publications from EMBL-EBI and pharmaceutical research at Novartis. Feedback loops involve transcription factors such as MYC and HIF1A, relationships probed in cancer centers like MD Anderson Cancer Center and metabolism studies at European Molecular Biology Laboratory (EMBL).
Hyperactivation via mutations in genes such as PIK3CA or loss of PTEN is implicated in many cancers studied at Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and consortiums like The Cancer Genome Atlas. Akt pathway dysregulation contributes to insulin resistance and type 2 diabetes research programs at Joslin Diabetes Center. Therapeutic targeting includes small-molecule inhibitors developed by industry leaders such as AstraZeneca, GlaxoSmithKline, and clinical trials coordinated by National Cancer Institute. Resistance mechanisms mediated by compensatory signaling through EGFR or HER2 have been documented in translational studies at Vanderbilt University Medical Center and UCSF Medical Center.
Biochemical assays pioneered at Salk Institute and University of Tokyo include kinase assays and lipid-binding studies; immunoblotting with phospho-specific antibodies developed in core facilities at University of Toronto and ETH Zurich detects activation. Imaging techniques employing confocal microscopy and FRET sensors were advanced by teams at Max Planck Institute for Biophysical Chemistry and University of California, Berkeley. Genetic manipulation via CRISPR/Cas9 optimized at Broad Institute and knockout mouse models from facilities at The Jackson Laboratory enable functional dissection. High-throughput sequencing and proteomics platforms at European Bioinformatics Institute and Proteome Research Centre provide mutation and phosphorylation landscape data.
Category:Cell signaling