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B cell antigen receptor-induced plasma membrane recruitment of the SH2 domain-containing inositol phosphatase is mediated by the protein tyrosine kinases Lyn and Syk

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Signals transduced by the B cell antigen receptor (BCR) are essential for B cell development and activation. Precise regulation of BCR signals is required to provide antigen-specific humoral immunity on one hand and tolerance of self proteins on the other hand. The SH2 domain-containing inositol 5' phosphatase (SHIP) is an important component for limiting antigen-induced signals in B cells. SHIP hydrolyzes the 5' phosphate of phosphatidyl-3,4,5-trisphosphate (PIP3) at the inner leaflet of the plasma membrane thereby disrupting binding motifs for the plextrine homology domains and attenuating the activities of Bruton's tyrosine kinase and phospholipase C-γ (PLC-γ2), respectively. Initially SHIP activation was believed to depend on inhibitory coreceptors like the Fc-γRIIB. However, studies using ship-/- DT40 cells or mice revealed that SHIP is activated downstream of BCR engagement in absence of Fcγ-RIIb also. The mechanism of BCR-induced SHIP activation and its relocalization towards the substrate PIP3, however, remains obscure to date. Here we report a real time imaging approach to analyze the molecular mechanism of BCR-induced SHIP relocalization. Interestingly, neither Fcg-RIIb nor the SHIP SH2 domain contributed to this process. Using genetic variants of DT40 B cells we could show that SHIP plasma membrane recruitment occurs upstream of PLC-γ2 activation. Our studies revealed that two apparently independent mechanisms are involved. First the Lyn-dependent assembly of a trimolecular complex comprising SHIP, the SH2 domain-containg adapter protein (Shc) and the growth factor receptor-bound protein 2 (Grb2) supports the SHIP relocalization. Second, the protein tyrosine kinase Syk is required for efficient SHIP plasma membrane recruitment.

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Correspondence to M Engelke.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Engelke, M., Li, X., Manno, B. et al. B cell antigen receptor-induced plasma membrane recruitment of the SH2 domain-containing inositol phosphatase is mediated by the protein tyrosine kinases Lyn and Syk. Cell Commun Signal 7, A73 (2009) doi:10.1186/1478-811X-7-S1-A73

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Keywords

  • Protein Tyrosine Kinase
  • DT40 Cell
  • Real Time Imaging
  • Cell Antigen
  • Ship Activation