The role of the vav proto-oncogene product in cell signalling

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Project objective

vav is a proto-oncogene expressed solely in hematopoietic cells. The protein has an array of structural features which suggests its participation in signal transduction. 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 with VAV are mostly unknown. The main objective of this proposal is the identification and functional role of transducing molecules interacting with VAV. Toward this goal I propose to use the two-hybrid system which I master. This aproach is specially suited for detecting newly interacting proteins. The validity of them can be demonstrated by in vitro aproach (i,e. fusion protein) and by in vivo experiments (coimmunprecipitation of the newly detected protein). The two-hybrid system has an added advantage: it permits to delimitate domains of the proteins responsible for the interaction. From my initial screen of the Iymphoid cell cDNA library with SH3/SH2/SH3 domains of VAV as bait, I have worked close to a 15% of the true positives. I have shown that nuclear proteins Ku-70, and probably RNP C, associates with VAV. I propose to evaluate the functional role/s of these interactions by different aproaches and to investigate changes of these interactions in resting and activated hematopoietic cells. We expect that these findings might help in understanding the function/s of VAV. To detect newly interacting proteins with VAV, I propose to characterize the remaining positives from my initial screen. We have evidences that an interaction of VAV and Grb2 exists by the two hybrid aproach and also in intact cells. This prompted my interest to investigate the interachon of a naturally occuring isoform -Grb3.3- which cannot bind tyr phosphorylated proteins, but retains intact SH3 domains. This is of general interest, becouse some evidences show the involvement of Grb3.3 in apoptosis. I propose to utilize the two-hybrid system to study the proteins interacting -in vivo- with Grb3.3. The positives will be identify and I hope to characterize new proteins which may be involved in the apoptotic pathway of Grb3.3.

Original text from CORDIS.

Participants

• INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · PARISCoordinatorFrance
• Not availableCity levelSpain

Links

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