BETA

How is phosphoinositide 3-kinase beta regulated by G-Protein Coupled Receptors and by Rab-5?

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 Obiettivo del progetto (Objective)

'Many signaling pathways in human cells involve lipid recognition events. The phosphorylation state of these lipids is under the control of both lipid kinases and lipid phosphatases. The phosphorylated second messenger lipids recruit lipid adaptor molecules, which regulate fundamental cellular processes including cell survival, proliferation, motility, differentiation and intracellular trafficking. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3’ hydroxyl group of inositol phosphate. The class IA PI3K family is associated with diseases including cancer, thrombosis, allergies and arthritis. Although it is clear that these PI3Ks are activated by Receptor Tyrosine Kinases (RTKs), PI3Kβ is the single member of the PI3Ks that is activated downstream of both RTKs and G-protein coupled receptors (GPCRs).

Using a combination of X-ray crystallography, in vitro activity assays and cellular experiments, I want to characterise the mechanisms specific to PI3Kß regulation. A first step will consist in the determination of PI3Kß structures in complex with G-protein ßγ heterodimers and with the small GTPase Rab5. That structural information will serve as an invaluable framework for further design of in vitro and cellular experiments to interrogate the exclusive mechanism of PI3Kβ regulation.

Because of the potential role of PI3Kβ in oncogenesis and thrombosis, I will also determine the structures of PI3Kß in complexes with a panel of PI3K isoform-specific inhibitors. These structures will provide the basis for the next generation of therapeutics.

This project will weave threads of structural, biophysical, biochemical and cell biology into a tapestry that depicts the roles of this unique enzyme that stands at the cross-road of RTK and GPCR signalling.'

Introduzione (Teaser)

Pioneering experiments have revealed a specific cellular target for cancer therapy. Blocking the interaction of two identified molecules stops cell transformation to a cancerous state and limits proliferation of cancerous cells.

Descrizione progetto (Article)

Phosphoinositide 3-kinases (PI3Ks) are a family of signal transduction enzymes. PI3K dysfunction is implicated in cancer through its roles in cell growth, proliferation and differentiation. EU-funded scientists launched the project 'How is phosphoinositide 3-kinase beta regulated by G-protein coupled receptors and by Rab-5?' (BETA) to enhance understanding of the PI3Kbeta pathway.

Activation of certain receptors in mammalian cell membranes stimulates release of molecules called Gbetagamma heterodimers that in turn have been identified as one of several activators of PI3Kbeta. In turn, PI3Kbeta phosphorylates its lipid substrate, initiating the signal cascade related to cellular functions including cell growth.

Scientists investigated the nature of the interaction between Gbetagamma and PI3Kbeta. The first step was to understand the structural interaction between PI3Kbeta and Gbetagamma heterodimers. Using advanced mass spectrometry, scientists identified regions of PI3Kbeta involved in either Gbetagamma or membrane lipid interactions. The researchers created a mutant that lost its ability to stimulate Gbetagamma but retained certain abilities related to cell growth.

The team utilised this mutant to show that the Gbetagamma-PI3Kbeta interaction is required for cell transformation to a cancerous state. Blocking the interaction reduced proliferation of tumour cells. These pioneering outcomes were published in the esteemed scientific journal 'Science Signaling' December 2012 with an illustration of the results chosen for the cover.

According to the World Health Organisation, cancer is the leading cause of death worldwide. A truly effective treatment would thus have inestimable impact on global health and the families devastated by this disease. The BETA project has established the Gbetagamma-PI3Kbeta interface as a target for cancer therapy, pointing the way to research and development for the next generation of cancer therapeutics.