PI3KACT · Dynamic regulation of Ras signaling – a novel way to attenuate PI3K activity in cancer and inflammation
FP7 — People (Marie Curie Actions)
- Duration
- 2011-01-01 → 2012-12-31
- EU contribution
- €172,065
- Participants
- 1
- Scheme
- MC-IIF
Lines connect the coordinator with its partners.
Results in brief
Dynamic regulation of Ras signaling - a novel way to attenuate PI3K activity in cancer and inflammation
Despite the growing knowledge concerning the inherent mechanisms driving inflammatory and allergic disease, present anti-inflammatory treatments mostly target symptoms or broadly suppress the immune system. Current medication displays little target cell selectivity, causes adverse effects, and impairs host defense. In allergy, mast cell activation is central to disease progression. We have demonstrated earlier, that phosphoinositide 3-kinase ? (PI3K?) is a central signalling enzyme in hematopoietic cell recruitment and mast cell degranulation. PI3K? is a heterodimer composed of a p110? catalytic and a p84 or p101 adapter subunit. The adapter subunits have distinct expression patterns: p101 is highly expressed in lymphocytes, macrophages and neutrophils, while p84 is the only adapter protein present in mast cells. Moreover, it was recently demonstrated that the p84/p110? PI3K? complex, but not the PI3K?. p101/p110? requires GTP-loaded Ras for its activation. We therefore proposed that the Ras-PI3K? axis could represent a promising target for a specific regulation of mast cell activity. In this project, we have shown that attenuation of Ras signalling using farnesyltransferase inhibitors (FTIs) interferes with various PI3K?-dependent functions of mast cells, such as the activation of protein kinase B (PKB/Akt), migration, and the release of histamine containing granules. PI3K?-dependent macrophage activation and migration were, however, maintained in the presence of FTIs. Our results demonstrate the important role of Ras in mast cell migration and activation, and represent a proof of concept for cell specific targeting of PI3K?. Moreover, we described a new mast cell specific phosphorylation event that regulates Ras-PI3K? interaction and therefore activation of mast cells. We have shown that upon IgE/antigen stimulation and Ca2+ influx a residue in the Ras binding domain of PI3K? becomes phosphorylated. This phosphorylation is mediated by PKCß and leads to the abrogation of Ras-PI3K? interaction. Altogether our results reveal a new approach to a fine-tuned control of PI3K?-dependent responses in mast cells, opening novel routes to alleviate allergic disease without general suppression of the immune system.
Data: CORDIS, © European Union
Project objective
Ras genes take a center stage in signal transduction and molecular oncology, where Ras-driven signaling pathways control proliferation, differentiation, cell adhesion, apoptosis, and cell migration. Mutations in RAS are very common in cancer, and have been found in 20-30% of all human tumors. Moreover, constitutive Ras activation is known to trigger senescence in the absence of “second hit” mutations (e.g. loss of p53). Interestingly, both processes - cancer progression and oncogene-induced cellular senescence - were shown to be dependent on Ras interaction with phosphoinositide 3-kinase (PI3K), which points to a dominant role of Ras-mediated PI3K activation in proliferative disease.Here we propose to investigate the possibility that Ras/PI3K interactions are dynamically regulated, which is supported by preliminary data: in certain cellular states, post-translational modification of Ras disrupts its binding to PI3K.We aim to elucidate the importance of this process in physiology and disease. We assume that regulated Ras interactions with PI3Kalpha act in cancer progression, while Ras/PI3Kgamma complexes transiently regulate inflammatory processes. Along these lines, we aim to uncover cellular signaling networks that dynamically dissociate Ras from PI3K. When the above mechanism is validated, we plan to study the consequences of the abrogation of Ras/PI3K interactions in “in vivo” mouse models. These will elucidate if and how PI3K detachment from Ras acts as a a general and central mechanism to balance inflammatory cell recruitment, oncogen-mediated metastasis, proliferation and senescence.
Original text from CORDIS.
Participants
- UNIVERSITAT BASEL · BaselCoordinatorSwitzerland
Links
Data: CORDIS, © European Union