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

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• 作者：Kathy W.K. Tse^a ; ¹ ; ^{kathytse.wk@gmail.com} ; Kevin B.L. Lin^a ; ² ; ^{kelin@bccrc.ca} ; May Dang-Lawson^a ; ^{mpdang@interchange.ubc.ca} ; Angel Guzman-Perez^b ; ^{angel.guzman-perez@pfizer.com} ; Gary E. Aspnes^b ; ^{gary.aspnes@pfizer.com} ; Leonard Buckbinder^b ; ^{leonard.buckbinder@pfizer.com} ; Michael R. Gold^a ; ^{mgold@mail.ubc.ca}
• 关键词：APC ; antigen presenting cell ; BCR ; B cell receptor ; FAK ; focal adhesion kinase ; ICAM-1 ; intercellular adhesion molecule-1 ; LFA-1 ; lymphocyte function-associated antigen-1 (伪L尾2 integrin) ; MZ ; marginal zone ; PI3K ; phosphoinositide 3-kinase ; P-Akt ; phosph
• 刊名：Cellular Immunology
• 出版年：2012
• 期刊代码：279_00088749
• 类别：med
• 出版时间：January-February, 2012
• 卷：275
• 期：1-2
• 页码：47-54
• 文件大小：460 K

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 (S1P). 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.