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

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Preventing cancer

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.

Health

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.

Keywords

Cancer therapy, transformation, Mammalian, receptor proteins, phosphoinositide 3-kinases, enzyme, Gbetagamma, mutant

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