P13K signalling; the rules of engagement

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Nearly all of the cells of our bodies contain three related proteins called PI3K alpha, PI3K beta and PI3K delta. We now know these PI3Ks play a very important role in transmitting information from hormones outside of the cell to the inside of cells. This information is needed for the cell to co-ordinate various complex responses to the hormone, such as cell growth, survival or movement. The key aim of this project is to define the roles for PI3Ks in a type of white blood cell called a neutrophil.

Publications

10 25 50
 
Description We have established that it is possible to use a genetic approach in mice to isolate specifc pi3k complexes from mouse tissues. previously this had proved very difficult because of technical issues with the use of bacterial DNA in mammalian cells, that we have now solved.
We have created a set of mice in which all class IA PI3K subunits that are widely expressed are endogenously avi-tagged. These have drive publications and on-going follow-on work in our lab funded by the MRC on prostate cancer and have been supplied to a number of other "international " labs to support their work. Eg Sabitini lab (Salk).
Exploitation Route This approach allows use of avi-tagging technology in mice to isolate any protein that is placed in frame with an avi-tag (15aa). It uses transgenically expressed BirA with mammalised codon usage (ROSA locus) to achieve efficient biotinylation of the tag in all mouse tissues tested. It has already been exported to a number of ther labs and underpins a lot of further work at BI on other funding. The apporach is very powerful and we are discussing further application with companies. We have obtained follow-on funding from the MRC to develop promising results on prostate cancer progression.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description They have been used by companies interested in selectively inhibiting class IA PI3K signalling pathways in cancer. We have also shown how class I PI3Ks can contribute to regulatory control of T cell attack on tumours and that this can combine with CSF1 signalling to support tumour progression . Dual inhibition of class IA PI3K and CSF1 signalling can lead to synergistic inhibition of tumour progression in some models.
First Year Of Impact 2017
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description MRC MICA project grant
Amount £950,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2018 
End 01/2022
 
Title Creation of PI3K avi-tag mice 
Description We introduced a 15 amino-acid Avi-tag into the C-terminus of endogenous genes encoding regulatory (p85alpha or p85beta) or catalytic (p110alpha, p110beta or p110delta) subunits of the Class IA PI3K family in mice. We also engineered expression of an optimised BirA (prokaryotic biotin ligase) expression cassette into the ROSA locus in mice and interbred these with the above Avi-tag mice. These mouse strains allow isolation of biotinylated Class IA PI3K subunits from mouse tissues and cell lines derived from them. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2018 
Provided To Others? Yes  
Impact First publications: PMID: 30442661 
 
Description Downward_RBD of Class I PI3Ks 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We designed the study and performed all experiments
Collaborator Contribution They provided genetically engineered mouse embryonic fibroblast cell lines with mutations in the Ras Binding Domain (RBD) of Class I PI3K alpha and beta.
Impact Houslay et al (2016) Sci Signal. 16;9(441):ra82. doi: 10.1126/scisignal.aae0453.
Start Year 2014
 
Description Steve Shuttleworth 
Organisation Karus Therapeutics
Country United Kingdom 
Sector Private 
PI Contribution We have performed research with neutrophils and xenografts and PI3K inhibitors and genetically modified mice to study the role of PI3Ks in immune function in inflammation and tumours.
Collaborator Contribution They have provided funding and inhibitors.
Impact See other outputs, some of the data is provided in the from of reports to Karus, some is published.
Start Year 2012
 
Description Invited lecturer to international meetings (average 2-3 per year) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact promoted discussions, collaborations

scientific collaborations, joint grants and publications
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019
 
Description Work experience for year 12 school students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Work shadowing for a yr 12 school student to understand biomedical research

Student applied and got an offer on a biomedical degree course
Year(s) Of Engagement Activity 2014