Completed Genetics & Molecular Biology Cancer

PI3K signalling; the rules of engagement.

Funder Wellcome Charity-funded
Recipient organisation Babraham Institute
Funding £1.3M
Period Jan 2009 — Jan 2016

In plain English

AI plain-English summary

Neutrophils—a type of immune cell—rely on a family of enzymes called PI3Ks to decide when to move, eat bacteria, or sound the alarm, but no one knows exactly which of the three related PI3K versions does what. This project aims to solve that puzzle. The researchers will use genetically engineered mice and selective drug-like molecules to systematically turn off or modify each PI3K in neutrophils, then watch what breaks. They will also swap parts of the enzymes between versions to pinpoint which molecular domains are essential for real-world function, and tag each PI3K with a tiny handle to track its location and binding partners inside the cell. This is fundamental science. There is no immediate clinical application. But PI3K signalling is already a target for cancer drugs and anti-inflammatory treatments, and neutrophils are central to everything from sepsis to arthritis. Understanding which PI3K variant controls which neutrophil behaviour could eventually guide the design of more precise drugs—ones that block harmful inflammation without crippling the immune system. Past fundamental work on PI3K structure, for example, directly enabled the development of the first approved PI3K inhibitor for leukaemia.

View original technical description
To use, PI3Kalpha-manipulated (conditional-KO and kinase-dead knock-in) mice and PI3Kalpha-selective, small-molecule inhibitors to define both the redundant and unique roles for PI3Kalpha in neutrophils. With our unpublished work on PI3Ksdelta and beta this will allow us to assemble the first integrated view of Class IA PI3K signalling in a specific cellular context. To establish which domains in the Class IA PI3Ks are critical to function in vivo; by expressing wild-type, point-mutated and chimeric-(carrying single domains switched with other members of the sub-family)-PI3Ks in PI3K-KO haemopoeitic stem cells and assessing their ability to rescue the established KO-phenotype in neutrophils. To make mice that have a common, small, high-affinity tag knocked-in to their endogenous PI3Kalpha, beta and delta and p85alpha and beta loci. To use neutrophils derived from the mice generated above to establish important factors governing the use of specific PI3Ks in neutrophil signalling. This will include defining, for each Class IA PI3K: (i) their quantity (ii) their regulatory and catalytic subunit composition, (iii) their binding to defined phosphotyrosine-containing adaptors, (iv) the identity of the signalling complexes in which they are found (v) the membrane compartments in which they operate at both macroscopic and EM-level resolution.

View the original record at the funder ↗

Researchers

Len Stephens (EPMC Awardee)

Related Research

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Class IA PI 3-kinase isoforms in oncogenic signalling
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Original classification

Programme Grant

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