Small molecule inhibitors of the Pyk2 and FAK kinases modulate chemoattractant-induced migration, adhesion and Akt activation in follicular and marginal zone B cells

被引:23
作者
Tse, Kathy W. K. [1 ,2 ]
Lin, Kevin B. L. [1 ,2 ]
Dang-Lawson, May [1 ,2 ]
Guzman-Perez, Angel [3 ]
Aspnes, Gary E. [3 ]
Buckbinder, Leonard [3 ]
Gold, Michael R. [1 ,2 ]
机构
[1] Univ British Columbia, Dept Microbiol & Immunol, Res Grp I3, Inst Life Sci, Vancouver, BC V6T 1Z3, Canada
[2] Univ British Columbia, Dept Microbiol & Immunol, CELL Res Grp, Inst Life Sci, Vancouver, BC V6T 1Z3, Canada
[3] Pfizer Global Res & Dev, Groton, CT 06340 USA
基金
加拿大健康研究院;
关键词
B cells; Marginal zone B cells; Pyk2; FAK; CXCL13; Sphingosine; 1-phosphate; Cell migration; Integrin-mediated adhesion; Akt; RICH TYROSINE KINASE-2; COSTIMULATORY MOLECULES; AUTOIMMUNE-DISEASES; LYMPHOID ORGANS; RAP GTPASES; T-CELLS; PHOSPHORYLATION; MICE; LYMPHOCYTES; CHEMOKINE;
D O I
10.1016/j.cellimm.2012.03.002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
B-lymphocytes produce protective antibodies but also contribute to autoimmunity. In particular, marginal zone (MZ) B cells recognize both microbial components and self-antigens. B cell trafficking is critical for B cell activation and is controlled by chemoattactants such as CXCL13 and sphingosine 1-phosphate (SIP). The related tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase (Pyk2) regulate cell migration and adhesion but their roles in B cells are not fully understood. Using a novel Pyk2-selective inhibitor described herein (PF-719), as well as a FAK-selective inhibitor, we show that both Pyk2 and FAK are important for CXCL13- and S1P-induced migration of B-2 cells and MZ B cells. In contrast, LFA-1-mediated adhesion required only Pyk2 whereas activation of the Akt pro-survival kinase required FAK but not Pyk2. Thus Pyk2 and FAK mediate critical processes in B cells and these inhibitors can be used to further elucidate their functions in B cells. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:47 / 54
页数:8
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