Simon obtained his first degree in Biochemistry at Heriot-Watt University in Edinburgh before moving to the John Innes Centre in Norwich where he studied for his PhD investigating the role of calcium signalling during legume symbiosis under the supervision of Professor J. Allan Downie
Simon then went to work as a postdoc for four years in Professor Pete Cullen's lab in the Department of Biochemistry at Bristol University where he investigated the GAP1 family of Ras GTPase-activating proteins.
Having become interested in the application of imaging technologies to answer biological questions Simon moved to the Babraham Institute in 2004 where he established the Institute's core Imaging Facility.
Over the last 20 years Simon has overseen the growth of the Facility which now provides access to a wide range of advanced imaging technologies including confocal microscopy, multi-photon microscopy, super resolution imaging, high content imaging and electron microscopy. The Facility is used by all the of the Institute's research programmes and an increasing number of external users from companies based on the Babraham Research Campus and the wider geographical area.
The PIP/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP/PI(3,4)P phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP/PI(3,4)P-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of YXXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP signaling, and supports tumor progression.
Rac-GTPases and their Rac-GEF activators play important roles in neutrophil-mediated host defence. These proteins control the adhesion molecules and cytoskeletal dynamics required for neutrophil recruitment to inflamed and infected organs, and the neutrophil effector responses that kill pathogens.
Gene duplication events can drive evolution by providing genetic material for new gene functions, and create opportunities for diverse developmental strategies to emerge between species. To study the contribution of duplicated genes to human early development, we examined the evolution and function of NANOGP1, a tandem duplicate of the transcription factor NANOG. We found that NANOGP1 and NANOG have overlapping but distinct expression profiles, with high NANOGP1 expression restricted to early epiblast cells and naïve-state pluripotent stem cells. Sequence analysis and epitope-tagging revealed that NANOGP1 is protein-coding with an intact homeobox domain. The duplication that created NANOGP1 occurred earlier in primate evolution than previously thought and has been retained only in great apes, whereas Old World monkeys have disabled the gene in different ways including homeodomain point mutations. NANOGP1 is a strong inducer of naïve pluripotency; however, unlike NANOG, it is not required to maintain the undifferentiated status of human naïve pluripotent cells. By retaining expression, sequence and partial functional conservation with its ancestral copy, NANOGP1 exemplifies how gene duplication and subfunctionalisation can contribute to transcription factor activity in human pluripotency and development.