Dr Tamara Chessa
Our lab has a long-standing interest in how PI3K signalling translates extracellular stimuli to different biological responses.The isoforms of Class IA PI3K carry out distinct functions,with PI3Kalpha being linked to cell growth/proliferation,PI3Kbeta to neutrophil/platelet biology,and PI3Kdelta to lymphocyte biology.Why,when many cells express all three isoforms capable of the same catalytic/adaptor function,does only one ClassIA heterodimer predominate in regulating a given cellular response?To address this question,we created mice carrying a biotinylation consensus sequence in the loci encoding the catalytic and regulatory subunits.In vivo biotinylated subunits will be subjected to streptavidin-mediated, rapid/specific pulldown from different tissues, followed by identification of signalling complexes by LC-MS/MS.This system opens up the possibility to dissect the ClassIA PI3K signalling cassette in different tumour types,ultimately aiming to identify novel drug targets in cancer.
Mass spectrometry (LC-MS/MS)
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Chessa TA*, Anderson KE*, Davidson K, Henderson RB, Walker S, Tolmachova T, Grys K, Rausch O, Seabra MC, Tybulewicz VL, Stephens LR, Hawkins PT (2010), PtdIns3P and Rac direct the assembly of the NADPH oxidase on a novel, pre-phagosomal compartment during FcR-mediated phagocytosis in primary mouse neutrophils, Blood 116(23):4978-4989 *These authors contributed equally to this work. Chessa TA, Anderson KE, Hu Y, Xu Q, Rausch O, Stephens LR, Hawkins PT (2010), Phosphorylation of threonine 154 in p40phox is an important physiological signal for activation of the neutrophil NADPH oxidase, Blood 116(26):6027-6036. Kulkarni S, Sitaru C, Jakus Z, Anderson KE, Damoulakis G, Davidson K, Hirose M, Juss J, Oxley D, Chessa TA, Ramadani F, Guillou H, Segonds-Pichon A, Fritsch A, Jarvis GE, Okkenhaug K, Ludwig R, Zillikens D, Mocsai A, Vanhaesebroeck B, Stephens LR, Hawkins PT (2011), PI3K? plays a critical role in neutrophil activation by immune complexes, Science Signalling 4(168): ra23.