Smad4-Ubiquitination by opposing E3 and DUB activi.. (Enzymes for Smad4-Ub)
Smad4-Ubiquitination by opposing E3 and DUB activities: a central control element in TGF-beta signaling
(Enzymes for Smad4-Ub)
Start date: Feb 1, 2009,
End date: Jan 31, 2011
The research here outlined deals with the relevance of ubiquitination in TGF-beta growth factor signalling. As outlined below (subchapters) TGF-beta signalling is fundamental for embryonic development and for a variety of human pathologies. In particular, recent data showed that tuning TGF-beta signalling is essential for differentiation of pluripotent cells and for cancer and metastasis. The proposal is therefore highly relevant not only scientifically but also for the socio-economic reasons. We will place emphasis of monoubiquitination as a mechanism to regulate protein function, which is a new concept emerging in signal transduction. Multidisiplinarity. As TGF-beta is such a pleiotropic cytokine, the research is highly multidisciplinary, ranging from biochemistry of the Smad4 signal transducer, to identification of new enzymes impinging on Smad4 ubiquitination levels, and how these events ultimately impact on the embryonic development and proliferative behaviour of adult cells. The reason for me to apply to this incoming international fellowship is to linked my specific expertise, that is, the ability to carry out special type of manipulations such as depletion of maternal mRNA in Xenopus oocytes (that are simply not present in Europe) or generation of transgenic frogs (poorly diffused). These technologies will be of help to the characterization of the embryonic phenotype of Smad4 modifying enzymes that are supplied maternally to the conceptus. Being the hosting laboratory a world leader in the TGF-beta signalling and embryonic development field, these expertise will now be able to spread in Europe. My own expertise will therefore integrate with those of the hosting group leading to a mutually beneficial and synergistic approach to a very complex and daring biological problem.
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