Signalling of new PI3 kinase isoforms

PI 3 kinases (PI3Ks) are central players in signal transduction and membrane trafficking pathways. They are involved in cancer, inflammation and autoimmunity. Although class I PI3Ks have been extensively studied and constitute attractive drug targets, little is known about class II PI3Ks (PI3K-C2). The primary goal of the EU-funded PI3K-C2-SIG (Signalling mechanisms of the class II isoforms of PI 3-kinase) project was to fill in the knowledge gap and elucidate the role of PI3K-C2 in intracellular trafficking.

Scientists generated novel transgenic mice with genetically inactivated PI3K-C2 isoforms. Since homozygous mice were embryonic lethal, they obtained conditional inactivating and heterozygous PI3K-C2a mice and tested the impact of silencing on various cell types including MEFs, keratinocytes, and macrophages. Considerable part of the project went into methodology optimisation and characterisation of these novel mouse lines.

Subsequent analysis at the cellular level revealed no apparent impact of PI3K-C2a on endocytosis or phagocytosis. However, high-resolution confocal microscopy showed that in the absence of PI3K-C2a, enlarged early endosomes formed within cells that were reminiscent of PI3P function loss. PI3P is a phospholipid associated with protein recruitment and implicated in protein trafficking.

To understand the role of PI3K-C2a on lipid signalling, researchers performed lipid profiling in cells with inactivated kinase. An additional project aim was to unveil the implication of the kinase in a metabolic context that is in the internalisation and trafficking of the insulin receptors.

Overall, the PI3K-C2-SIG study has highlighted the importance of PI3K-C in various signalling transduction pathways with clinical implications. Drug development efforts towards new PI3K inhibitors and activators may improve the treatment of infectious diseases and cancer.