Graeme Guy obtained a degree in pharmacy in New Zealand and practiced there for several years before returning to University to pursue higher degrees. He obtained his MSc from the University of Waikato in New Zealand and his PhD in Adelaide, Australia. He then spent 5 years as a post-doctoral fellow at the University of Birmingham, in the UK before coming to IMCB. Graeme has always pursued a general interest in Cell Signalling, with specific interests in Tumor Necrosis Factor (TNF) and Fibroblast Growth Factor (FGF) initiated pathways. In recent years his laboratory has worked on a family of inhibitor proteins of the key Ras/MAP kinase pathway, which is involved in many aspects of growth and differentiation of cells and is deregulated in many cancers.

The research interest of the lab is broadly centred around in signal transduction with a specific focus on FGF and specifically with novel proteins that modulate the Ras/MARK pathway in FGF signalling and other pathways. Ras/MARK pathway is central to proliferation and differentiation and represents a major drug target in respect to cancer treatment.

Previous research
We chose to work initially on the FGF signalling pathway as this was the least-well characterized of the EGF, PDGF, FGF triumvirate of receptor tyrosine kinases. We targeted a missing scaffold protein which was later named FRS2, and was involved in a lot of early characterisation of FRS2 and the specifie interaction of novel proteins the regulate the Ras/MARK pathway downstream of FGFR and other pathways in conjunction with Yossi Schlessinger’s lab.
 Several years ago a novel protein was discovered in the in the context of FGF-signalling in Drosophila that was induced by the Ras/Erk pathway and acted back on the pathway in a classic feedback inhibition mechanism. The protein was termed Sprouty as its absence caused excessive branching (sprouting) in the tracheal system. There are four mammalian Sprouty (Spry) proteins that share a large and several small sequence similarities. The large cysteine-rich domain is shared with another family of proteins, called Spreds that consists of three isoforms. Two of the Spred proteins have also been shown to inhibit the Ras/Erk pathway but by an apparently different mode of action to the Spry proteins.
Our aim has been to elucidate the biology and mode of action of the Spry and Spred isoforms. The Spry, and to a lesser degree the Spred, proteins have created a lot of interest as they are in a prime position to control a central signaling pathway that contains a number of notable oncogene products. With the latter thought in mind we screened a number of cancers for trends in Spry gene expression. We discovered a fairly universal down-regulation of both Spry1 and 2 genes in breast cancer. A subsequent collaborative project also detailed the downregulation of Spry2 in liver cancer. Currently we are the most prolific group in publishing on both the physiological and biochemical characterization of Spry isoforms (mainly Spry2) in journals such as: EMBO, EMBO Reports, Mol. Cell Biol and J. Biol Chem.

Current and Future research

Spred: We are currently pursuing the interaction of Spred1 with 2 proteins with the neurosystem. With this in mind we are setting up a collaboration with Dr Christoph Winkler of DBS to look at the role of Spred1/2 in Zebrafish nerve development.

Sprouty: The role of Spry2 is currently being investigated: on two fronts; biochemical (biophysical) and physiological involving animal models. The physiological link between Sprys and c-Cbl is being explored further. We have ongoing work showing Spry2 impacts on cell cycle kinases and this work will be taken to publication level. The involvement of Sprys in various cancers and especially recent data showing Spry expression in senescence will be developed. The biochemical data showing Sprys inhibit transformation of an oncogene PyMT transfected cells will be examined in mouse models whereby mammary epithelial tumor cells from transgenic mice expressing Spry2 will be examined on a background of PyMT-induced breast cancer to investigate a putative tumor suppressive role for Spry2, especially in a breast cancer context in vivo.