The role of the Syk/Shp-1 kinase-phosphatase equilibrium in B cell development and signalling
04.06.2014
Alsadeq A, Hobeika E, Medgyesi D, Kläsener K, Reth M.
J Immunol. 2014;193(1):268-76.
Signal transduction from the B cell antigen receptor (BCR) is regulated by the equilibrium between kinases (e.g. Syk) and phosphatases (e.g. Shp-1). Previous studies showed that Syk-deficient B cells have a developmental block at the pro-/pre-B cell stage whereas a B cell-specific Shp-1 deficiency promoted B-1a cell development and led to autoimmunity. We generated B cell-specific Shp-1 and Syk double knockout (DKO) mice and compared them to the single KO mice deficient for either Syk or Shp-1. Unlike Syk-deficient mice, the DKO mice can generate mature B cells, albeit at more than 20-fold reduced B cell numbers. The DKO B-2 cells are all Syk-negative whereas the peritoneal DKO B-1 cells still express Syk indicating that they require this kinase for their proper development. The DKO B-2 cells cannot be stimulated via the BCR, whereas they are efficiently activated via toll-like receptors (TLR) or CD40. We also found that in DKO pre-B cells the kinase Zap-70 is associated to the pre-BCR, suggesting that Zap-70 is important to promote B cell maturation in the absence of Syk and SHP-1. Together, our data show that a properly balanced kinase/phosphatase equilibrium is crucial for normal B cell development and function.
