Research / Clinical Summary

Nicholas Webster, PhD, MA, BA Professor IR, Medicine Cancer Genetics Program Contact by Email

Our research focuses on the mechanisms of signal transduction from G-protein coupled and tyrosine kinase receptors with particular emphasis on the gonadotropin-releasing hormone receptor and the insulin/IGF-I receptors. One project concerns the activation of gonadotropin genes in pituitary gonadotrope model systems via activation of the GnRH receptor. GnRH stimulates the ERK cascade leading to the induction of c-fos and LHb protein expression in LbT2 cells. We have shown that the GnRH receptor couples to both Gs and Gq and that both pathways contribute to activation of ERK and induction of c-fos and LHb proteins. This is relevant to cancer research as GnRH agopnists are used to treat a number of gynaecological cancers. Another project involves the activation of phospholipase C signaling by the insulin receptor. We have shown that the IR stimulates PLCg activity in a number of cells and this activation is necessary for glucose transport and GLUT4 translocation, as well as mitogenesis and cellular proliferation. We are currently investigating which phosphotyrosine residues in the insulin receptor interact with PLCg, and how this interaction stimulates PLC activity in the absence of phosphorylation of PLCg. We are also looking for downstream targets of PLC signaling that might be involved in insulin action. A third project concerns the mechanism of activation of the IR by small molecule insulin mimetics. We have shown that DAQ-B1, a small molecule activator originally isolated by Merck, activates the IR in-vitro and in-vivo. We have also identified two new insulin mimetics that have similar activity. The mimetics are partial agonists for the IR and signal selectively, being more potent activators of PI-3Kinase than ras-MAPK signaling. The mechanisms underlying this selectivity are being investigated. We have also developed a high-throughput screen for insulin receptor activators that we are using in collaboration with a synthetic chemist at Duke University to identify more potent and selective activators. An interesting feature of these agents is that they lack the proliferative effect of insulin so would be useful agents where insulin therapy might cause unwanted proliferation of cells. A fourth project concerns the post-transcriptional regulation of alternative splicing. The model system that we investigate is the insulin receptor. Two distinct IR isoforms are generated from a single gene. The two isoforms differ in the presence of a small 36-nucleotide exon in the C-terminus of the alpha-subunit. The fetal form of the receptor lacking exon 11, binds insulin and IGF-II with high affinity and is similar to insulin/IGF receptors that have been cloned from lower organisms where insulin is a growth factor. Exon 11 has arisen later in evolution and prevents the binding of IGF-II to the IR. This isoform containing exon 11 is expressed in adult tissues involved in regulating metabolism. It is interesting to speculate that the appearance of this exon coincided with the use of insulin to control metabolism rather than growth.

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