Skip to main content

PI3K isoform specific functions in the nucleus

Final Activity Report Summary - PI3K IN THE NUCLEUS (PI3K isoform specific functions in the nucleus)

In this project, we have investigated the roles of the class IA PI3K isoforms in the nucleus of a cell-model system. The chosen model was the macrophage, a white blood cell type that is important in inflammation and cancer and express all class I PI3Ks.

The aim of the re-integration project was to delineate the role of the PI3K isoforms in the nucleus and to establish a potential PI3K isoform-specific controlled pathway that links nuclear with cytosolic signalling in the context of the Rho small GTPase proteins.

More specifically, the objectives of this project were:
1. Characterisation of expression and function of the nuclear PI3K isoforms in macrophages carrying mutant class IA PI3Ks.
2. Investigation of a potential PI3K isoform specific PTEN-dependent regulation of Akt phosphorylation in the nucleus.
3. Investigation of a potential PI3K-isoform specific regulation of cross-talk between CKIs and Rho GTPases
4. Investigation of the mechanism that controls the translocation of p110s into the nucleus and identification of the nuclear import/export sequences in the p110s sequence.

We have discovered for the first time that there is a CSF-1R signalling in the nucleus which is triggered by extracellular CSF-1 and that the distinct PI3K isoforms play individual roles in the nuclear compartment. This was also the first investigation of the involvement of PI3Ks in the concomitant regulation of cell-cycle and migration. We have found that the p110d PI3K isoform specifically functions in the nucleus of macrophages and links the nuclear with cytosolic signalling. This will contribute to exploiting therapeutic strategies which by targeting one molecule, inhibition of both, cell proliferation and metastasis can be achieved. The identification of a particular PI3K isoform that specifically controls cell cycle and migration might lead the way to the development of potent and selective inhibitors for anti-cancer therapy.