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

• Published in: Blood Vol. 117; no. 5; pp. 1574 - 1584
• Main Authors: Pearce, Glen, Audzevich, Tatsiana, Jessberger, Rolf
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 03.02.2011; Americain Society of Hematology
• Subjects: Actins - metabolism; Animals; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Biological and medical sciences; Blotting, Western; Cell Movement; DNA-Binding Proteins - physiology; Flow Cytometry; Guanine Nucleotide Exchange Factors - physiology; Hematologic and hematopoietic diseases; Immunoprecipitation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - isolation & purification; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Mice; Minor Histocompatibility Antigens; Nuclear Proteins - physiology; Phosphorylation; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - isolation & purification; Protein-Tyrosine Kinases - metabolism; Syk Kinase; Tyrosine - metabolism; Cell motility; Phosphorylation; Hematology; Enzyme; Transferases; B-Lymphocyte; Tyrosine protein kinase Syk; Protein-tyrosine kinase; Cell migration; Protein
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-07-295659

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.