Integrated cellular signalling and PI3K isoforms
of our research axis
The team directed by J Guillermet-Guibert studies the family of lipid kinases known as phosphoinositide 3-kinases (PI3Ks) from different angles. This family of enzymes is involved in major cellular functions such as cell survival, proliferation, growth, migration, differentiation but also protein synthesis and intracellular vesicular trafficking. In vertebrates, the PI3K family is divided into three different classes. This classification is based on their structure, mode of activation and lipid substrate specificity in vitro and in vivo. These enzymes, encoded by 8 different genes, all phosphorylate the hydroxyl group in position 3 of the inositol ring of phosphoinositides, hence their name.
Only class I (composed of PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ) can convert phosphatidylinositol (4,5)-bisphosphate [PtdIns-4,5-P2, PtdIns (4,5) P2, PIP2] to phosphatidylinositol (3,4,5)-trisphosphate [PtdIns-3,4,5-P3, PtdIns (3,4,5) P3, PIP3]. The substrate of class I enzymes is mainly located at the cell membrane. Thus, activation of class I PI3Ks produces a lipid second messenger at the plasma membrane at the interface with the cytoplasm, which allows the transmission of biochemical information into the cytoplasm and leads to a cellular response.
Class II (PI3KC2α, PI3KC2β, PI3KC2γ) and class III (VPS34) PI3Ks can generate phosphatidylinositol 3-phosphate [PtdIns-3-P, PtdIns (3) P, PI-3-P]. Class II PI3Ks can also synthesise phosphatidylinositol (3,4)-bisphosphate [PtdIns-3, 4-P2, PtdIns (3,4) P2]. The substrates of these enzymes are present in the outer membranes of organelles within the cell, at the level of endosomes, autophagosomes. Thus, class II and III PI3Ks control intracellular vesicular trafficking.
The high activation of class I PI3Ks is considered to be a characteristic of cancer; however, the role of each class I PI3K in the different stages of carcinogenesis is poorly understood. This research is carried out by our team.
The roles of class II and III PI3Ks in cancer are poorly studied. We have undertaken to understand them.
We mostly apply our research to solid cancers such as pancreatic cancer to better understand, earlier diagnose and treat this deadly disease. We also work on ovarian cancers and collaborate with teams working on liquid cancers.
Genetically modified mice
Dr B Thibault and Dr M Dufresne
Dr M Delarue and D M Di-Luoffo
Dr C Basset
PARTERNSHIPS & FUNDING
Centre de Recherches en Cancérologie de Toulouse (Oncopole)
Toulouse – FR
05 82 74 15 75
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