SYK regulates B-cell migration by phosphorylation of the F-actin interacting protein SWAP-70

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BlankBlood, 3 February 2011, Vol. 117, No. 5, pp. 1574-1584.

SYK regulates B-cell migration by phosphorylation of the F-actin interacting

protein SWAP-70

Glen Pearce1, Tatsiana Audzevich1, and Rolf Jessberger1

1 Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus,

Dresden University of Technology, Dresden, Germany

B-cell migration into and within lymphoid tissues is not only central to the

humoral immune response but also for the development of malignancies and

autoimmunity. We previously demonstrated that SWAP-70, an F-actin-binding, Rho

GTPase-interacting protein strongly expressed in activated B cells, is necessary

for normal B-cell migration in vivo. SWAP-70 regulates integrin-mediated

adhesion and cell attachment. Here we show that upon B-cell activation, SWAP-70

is extensively posttranslationally modified and becomes tyrosine phosphorylated

by SYK at position 517. This phosphorylation inhibits binding of SWAP-70 to

F-actin. Phospho-site mutants of SWAP-70 disrupt B-cell polarization in a

dominant-negative fashion in vitro and impair migration in vivo. After CXCL12

stimulation of B cells SYK becomes activated and SWAP-70 is phosphorylated in a

SYK-dependent manner. Use of the highly specific SYK inhibitor BAY61-3606 showed

SYK activity is necessary for normal chemotaxis and B-cell polarization in vitro

and for entry of B cells into lymph nodes in vivo. These findings demonstrate a

novel requirement for SYK in migration and polarization of naive recirculating B

cells and show that SWAP-70 is an important target of SYK in this pathway.