TY  - THES
AB  - The intracellular processing of B cell antigen receptor (BCR) delivered signals is essential for the development and activation of B lymphocytes. A central element of the BCR signaling cascade is the BCR-induced mobilization of Ca2+. The molecular basis of this process is the formation of the so-called Ca2+ initiation complex, a signalosome based on the adaptor protein SLP-65. Although the structure of this signaling complex and the functional interactions of the protein components have extensively been characterized, a central question of its function has not yet been understood. How does the cytoplasmic adaptor protein SLP-65, as the scaffolding for the Ca2+ initiation complex, mediate the spatial integration of this signaling unit into the BCR-proximal signaling cascade at the plasma membrane? In the present study, it was possible to observe this process, for the first time, in vivo by means of imaging techniques: Depending on the concerted action of the N-terminal leucine zipper motif and the C-terminal SH2 domain, SLP-65 relocalizes BCR-induced out of the cytosol to the plasma membrane. In this process tyrosine phosphorylation of SLP-65 is not necessary. A negative regulation of the Ca2+ mobilization by the adaptor protein Grb2 also requires an integration of this cytoplasmic protein into the BCR signaling cascade. But neither the subcellular organization, nor the function of the Ca2+-inhibiting Grb2 signaling module is known. In this study it was possible to demonstrate that the negative regulation of a Ca2+ mobilization by the adaptor protein Grb2 in immature B cells is connected to its BCR-induced plasma membrane relocalization. The phosphotyrosine-mediated recruitment of Grb2 to the plasma membrane-associated adaptor protein Dok-3 was identified as the basis of Grb2 function. The interaction of the C-terminal Grb2 SH3 domain together with Dok-3-intrinsic features at the plasma membrane is decisive for the Ca2+-regulatory effect of the Dok-3/Grb2 signaling module. The results of this study show the dynamic spatial organization of central signal modules downstream of BCR signaling in vivo. The concerted process of subcellular localization and signaling function of protein modules emphasizes the essential significance of spatial coordination of signaling processes by adaptor proteins.
DA  - 2007
KW  - B-Lymphozyt , Adaptorproteine , Signaltransduktion , Plasmamembran , Lokalisation , B-Lymphozyten-Rezeptor , Grün fluoreszierendes Protein , B-Zellen , SLP-65 , Grb2 (Growth factor receptor-bound protein 2) , Dok-3 (Downstream of tyrosine kinase 3) ,
LA  - ger
PY  - 2007
TI  - Studien zur subzellulären Navigation von Signalmolekülen der Ca2+-Antwort in aktivierten B-Lymphocyten
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:361-12523
Y2  - 2024-11-22T11:43:52
ER  -