PI3K IN THE NUCLEUS · PI3K isoform specific functions in the nucleus
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-03-01 → 2008-02-29
- EU contribution
- €40,000
- Participants
- 1
- Scheme
- ERG
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
During my Marie Curie fellowship, I have found that the p110d PI 3-kinase (PI3K) selectively regulates the cell migration and proliferation of mouse macrophages and I have delineated the signalling pathway by which p110d regulates these responses. In particular, the CSF-1-induced signalling found to be mainly controlled by p110d due to its unexpected preferential recruitment to the CSF-1 receptor.Interestingly, RhoA activity was found to be selectively controlled by p110d and to be the key molecule that regulates both, proliferation (through PTEN) and migration. I have also obtained evidence for a new pathway of interplay between cytoskeletal regulation and cell cycle, with an unexpected potential role for PI3K in the nucleus. It is the latter aspect that I propose for my return grant application.The aim of the proposed return project is 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 the present project are:- Characterization of expression and function of the nuclear PI3K isoforms in macrophages carrying mutant class IA PI3Ks.- Investigation of a potential PI3K isoform specific PTEN-dependent regulation of Akt phosphorylation in the nucleus.- Investigation of a potential PI3K-isoform specific regulation of cross-talk between CKIs and Rho GTPases- 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.This reintegration grant will assist me to carry out work in this subject area as an independent researcher upon my return to my country of origin (Greece) and will allow me to continue my collaboration with Dr. Vanhaesebroeck who is a world-expert in PI3K signalling.
Original text from CORDIS.
Participants
- UNIVERSITY OF CRETE/FACULTY OF MEDICINE · HERAKLIONCoordinatorCity levelGreece
Links
Data: CORDIS, © European Union