PI3K signalling: the path to discovery and understanding

@article{Vanhaesebroeck2012PI3KST,
  title={PI3K signalling: the path to discovery and understanding},
  author={Bart Vanhaesebroeck and Len R. Stephens and Phillip T. Hawkins},
  journal={Nature Reviews Molecular Cell Biology},
  year={2012},
  volume={13},
  pages={195-203}
}
Over the past two decades, our understanding of phospoinositide 3-kinases (PI3Ks) has progressed from the identification of an enzymatic activity associated with growth factors, GPCRs and certain oncogene products to a disease target in cancer and inflammation, with PI3K inhibitors currently in clinical trials. Elucidation of PI3K-dependent networks led to the discovery of the phosphoinositide-binding PH, PX and FYVE domains as conduits of intracellular lipid signalling, the determination of… 
PI3King the right partner: unique interactions and signaling by p110β.
  • H. Dbouk
  • Medicine
    Postdoc journal : a journal of postdoctoral research and postdoctoral affairs
  • 2015
TLDR
Recent studies have characterized these p110β interacting partners, defining the binding mechanisms and regulation, and thus provide insight into the function of this kinase in physiology and disease.
Novel approaches to inhibitor design for the p110β phosphoinositide 3-kinase.
TLDR
Recent discoveries regarding the regulatory mechanisms that control p110β activity suggest alternative strategies by which to disrupt signaling by this PI 3-kinase isoform, and how these new insights into p110 regulation might be used to devise novel pharmacological inhibitors are discussed.
Targeting PI3K signaling in cancer: Challenges and advances.
TLDR
The effort to develop isoform-specific inhibitors, together with novel therapeutic strategies aimed at reducing the toxicity and adverse effects, opened a new promising era for PI3K inhibitors.
Inositol Polyphosphate-Based Compounds as Inhibitors of Phosphoinositide 3-Kinase-Dependent Signaling
TLDR
This review summarizes previously published studies that led to the identification of inositol polyphosphates as promising parent molecules to design novel inhibitors of PI3K-dependent signals and focuses on the inhibition of protein–membrane interactions mediated by binding of pleckstrin homology domains and phosphoinositides that was proposed 20 years ago.
Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities
TLDR
The current state of PI3K isoform-selective inhibitor development is described, the structure of SHIP-1 is focused on and its function in the immune system is considered, and the state of small molecule compounds that potently and selectively modulate SHIP activity are considered.
PIK3CA in cancer: The past 30 years.
TLDR
In the fourth decade of research, PI3K-based cancer drugs will continue to emerge, as will new knowledge regarding other uncovered functions of this protein and pathway.
PI3K and AKT: Unfaithful Partners in Cancer
TLDR
The complex relationship between PI3K and AKT in cancer is highlighted and the consequences for cancer therapy are discussed, revealing another level of complexity in this pathway.
The Hidden Conundrum of Phosphoinositide Signaling in Cancer.
TLDR
How PI(4,5)P2 and PIP kinases serve as a proximal node in phosphoinositide signaling axis and how its interaction with cytoskeletal proteins regulates migratory and invasive nexus of metastasizing tumor cells is highlighted.
Targeting phosphatidylinositol 3‐kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors
TLDR
An overview of the structural features of PI3Kγ that influence γ‐isoform selectivity and the structure‐selectivity‐activity relationship of existing clinical PI3 Kγ inhibitors is provided and the experimental and computational techniques utilized to identify PI3kγ inhibitors are summarized.
Classes of phosphoinositide 3-kinases at a glance
TLDR
The biochemical activities, cellular roles and functional requirements for the three classes of PI3Ks are summarized to provide an overview of the parallels, the key differences and crucial interplays between the regulation and roles of the three PI3k classes.
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References

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The p110δ crystal structure uncovers mechanisms for selectivity and potency of novel PI3K inhibitors
TLDR
Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI3K inhibitors reveal that selectivity towards p110δ can be achieved by exploiting its conformational flexibility and the sequence diversity of active-site residues that do not contact ATP.
The emerging mechanisms of isoform-specific PI3K signalling
TLDR
A better understanding of how the different PI3K isoforms are regulated and control signalling could uncover their roles in pathology and reveal in which disease contexts their blockade could be most beneficial.
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TLDR
A study of the relation of structure to function for sequence motifs defined through the use of homology searches and protein modelling techniques is described and used to assign the family of phosphoinositide kinases to subgroups.
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TLDR
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TLDR
The 2.2 Å X-ray crystallographic structure of the catalytic subunit of PI3Kγ, the class I enzyme that is activated by heterotrimeric G-protein βγ subunits and Ras is reported.
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TLDR
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TLDR
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TLDR
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TLDR
A family of PI 3-kinases in Drosophila, including a novel class represented by PI3K_68D, has the potential to bind to signalling molecules containing SH3 domains, lacks p85-adaptor-binding sequences, has a Ca(2+)-independent phospholipid-binding domain and displays a restricted in vitro substrate specificity, so it could define a novel signal transduction pathway.
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TLDR
It is found that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110 alpha activity, which illustrates systematic target validation using a matrix of inhibitors that span a protein family.
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