Research objectives and content Thyrotropin (TSH) receptor mediate proliferation of thyroid cells and is implicated in hormone secretion, differentiation and tumorigenesis of these cells. TSH acts through a serpentine receptor which has been shown to couple with the heterotrimeric G-proteins Gs, Gq, Gi, G12 and G13 and to activate two main intracellular effectors: cAMP and the proto-oncogene Ras. Recently, G-protein coupled receptors have been shown to regulate cell morphology, growth, survival and transformation through the activation of specific heterotrimeric G-proteins. Depending on the G-protein coupled, distinct signal transduction pathways can be activated. It has been shown that tyrosine phosphorylation of focal adhesion proteins (paxillin, p130Cas, pl25FAK, src), kinase activity of pl25FAK, src, P13K PKC and activation of Ras family GTP-binding proteins (Ras, Rho, Rac and CDC42) can be stimulated through G-protein coupled receptors. Interestingly, these substrates have been shown to be activated and control critical molecular events in signal transduction pathways involved in the action of integrins, growth factor receptors and oncogenes. With this project we plan to identify new signalling components which can be involved in transduction pathways regulating thyroid cell growth through the activation of TSH receptor. We plan to elucidate the molecular events involved in Ras activation following TSH stimulation. In particular, we aim to examine tyrosine phosphorylation of focal adhesion proteins (paxillin, pl30Cas, Shc, p125FAK, src) in response to TSH and whether these substrates are involved in formation of molecular complexes with signalling and adaptor proteins (Grb2, Crk) following TSH-induced tyrosine phosphorylation. We plan to explore also the role of Rho, PI3K and PKC in TSH receptor signalling and to study the involvement of these signalling proteins in Ras activation and cell proliferation of TSHstimulated thyroid cells. Training Content (objective benefit and expected impact)
This project aims to identify new molecular targets in thyroid tumorigenesis whlch could be of potential use in cancer therapy. The practical experience and scientific knowledge that I have gained during my previous position will help in As a result of this, fresh ideas and technologies will be imported in a less-favoured region of the Community and new scientific collaborations will also be initiated.
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