Abstract FR:

Lymphocyte antigen receptor engagement triggers activation of various signaling cascades, initiated by sequential activation of the Src and Syk families of protein tyrosine kinases, and leading to gene transcription. Although they lack both enzymatic and transcriptional activity, adaptor proteins are crucial for this process. The cytoplasmic adaptor protein 3BP2 contains a PH domain, proline–rich regions, and a SH2 domain, and interacts with Syk kinases, the LAT adaptor and the PLCg. 3BP2 plays a positive role in NK cytotoxicity, in basophilic degranulation, and activation of NFAT and AP-1 transcription factors leading to interleukine-2 gene transcription in T cells. Finally, point mutations in 3bp2 gene leads to cherubism, a human pathology related to bone development. 3BP2 thus seems to have an important function in hematopoietic cells. In order to better understand its role in lymphocytes, we looked for and identified novel 3BP2 interacting partners. Among those are essential proteins for lymphocyte signaling like HIP-55 and CIN85 and nucleotidic exchange factors Vav1 and Vav2. We showed that 3BP2 interacts with SH3 domain of HIP-55 or CIN85 by the different proline rich domains, and that the interaction is required for endocytosis and regulation of actin. Moreover, our data indicate that the basal interaction between 3BP2 and Vav family members, mediated by the first proline-rich domain of 3BP2 and a SH3 domain of Vav, is reinforced in a phosphotyrosine-dependent way upon immunoreceptors stimulation in T and B cells. We show that there is a functional cooperation between 3BP2 and Vav family members in small GTPase Rac and NFAT transcription activation in lymphocytes. Finally, a differential exression of 3BP3 is observed in Th1 type lymphocytes. And also, the retroviral overexpression of 3BP2 in primary T lymphocytes accelerates the Th1 type cytokines synthesis and the activation induced cell death. These results suggest 3BP2’s implication in T lymphocyte differentiation and its role in the regulation of cell survival. These results suggest that 3BP2 allows the formation of various multimolecular complexes, and might take part in the regulation of different signaling pathway activated in lymphocytes during immune response.