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Structural and functional characterization of proteins partners of vavprotooncogene


Research objectives and content
The objective of my proposal is to characterize new partners of the proto-oncogene Vav, in order to learn more of its role in signalling pathways. vav is expressed mainly in cells of hematopoietic origin and displays a complex array of structural motifs that implicated Vav as an adaptor linking cell surface receptor to downstream signalling cascade. Although the analysis of mice deficient in vav expression (vav-/- ) has shown the essential role of this proto-oncogene in T and B cell proliferation, the downstream signalling molecules associated to Vav are mostly unknown. To identify new transducing molecules interacting with Vav I used the SH3-SH2-SH3 domains of Vav to screen a lymphoid cell cDNA library by the yeast two-hybrid system and I isolated humSiah2, a new human homolog of the Drosophila Seven in Absentia gene (Sina). Sina encodes a ringfinger-containing nuclear protein reqtured for the correct integration of signal transduction downstream of the tyrosine kinase receptor sevenless during R7 photoreceptor development. At the moment the role of Sina/humSiah2 proteins is unknown. Further characterization of the signalling pathways in which they participate are also required. I will start by characterizing Vav/humsiah2 interaction in an in vivo context by coimmunoprecipitation and coimmunolocalization experiments. In the same time I will develop studies aimed at understanding the functional role of humSiah2 in order to clarify the biological significance of humSiah2/Vav interaction and to precise the pathways in which both proteins are involved. For this purpose I propose to investigate: a) the modulation of humSiah2 expression and localization in resting and activated hematopoietic cells; b) the effect of the overexpression of exogenous humSiah2 in hematopoietic cells (and its possible implication in the proliferation and differentiation); c) its role as a transcriptional regulator (several ring-finger containing proteins have been implicated in this process). To further understand the role of humSiah2. I will perform a two-hybrid screen with humSiah2 as a bait.
Training content (objective, benefit and expected impact)
The continuation and the fulfilment of the training at the U363 in Paris will be very useful for my return to the Department of Histology and Medical embryology in Italy. The research interests of this Department in Rome are mainly oriented to study the control of cell cycle and apoptosis. Investigators at U363 have developed different lines of research to study signal transduction in normal and transformed cells. The training in the INSERM U363 will give me a remarkable expertise in molecular and cellular biology techniques and will allow to improve my scientific qualification and knowledge regarding the mechanisms that control cell proliferation and differentiation. All this will give me the possibility to come back to the Department of Histology and Medical Embryology in Italy to contribute with the knowledge of the experience obtained to the development of this Department.
Links with industry / industrial relevance (22)
Although there is no direct industrial, economical and/or social interest associated with this project, the definition of functional roles for both Vav and humSiah2 in the hematopoietic lineage, could give new links with hematopoietic disorders. In this case. it will be very useful to investigate their potential role in vivo in proliferation and differentiation of megakaryocytic lineage.


Institut National de la Santé et de la Recherche Médicale
27,Rue Du Faubourg Saint-jacques
75014 Paris