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

TseK.W.K.; LinK.B.L.; Dang-LawsonM.; Guzman-PerezA.; AspnesG.E.; BuckbinderL.; GoldM.R.

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

机译：Pyk2和FAK激酶的小分子抑制剂调节滤泡和边缘区B细胞中趋化因子诱导的迁移，粘附和Akt活化

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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.

机译：B淋巴细胞产生保护性抗体，但也有助于自身免疫。特别是，边缘区（MZ）B细胞同时识别微生物成分和自身抗原。 B细胞的运输对于B细胞的活化至关重要，并受化学反应物（例如CXCL13和1磷酸鞘氨醇（S1P））控制。相关的酪氨酸激酶局灶性粘附激酶（FAK）和富含脯氨酸的酪氨酸激酶（Pyk2）调节细胞迁移和粘附，但它们在B细胞中的作用尚不完全清楚。使用本文所述的新型Pyk2选择性抑制剂（PF-719）和FAK选择性抑制剂，我们证明Pyk2和FAK均对CXCL13和S1P诱导的B-2细胞和MZ B细胞迁移具有重要作用。相反，LFA-1介导的粘附仅需要Pyk2，而Akt促存活激酶的激活则需要FAK，而不需要Pyk2。因此，Pyk2和FAK介导B细胞中的关键过程，这些抑制剂可用于进一步阐明其在B细胞中的功能。

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《Cellular immunology》 |2012年第2期|共8页
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TseK.W.K.; LinK.B.L.; Dang-LawsonM.; Guzman-PerezA.; AspnesG.E.; BuckbinderL.; GoldM.R.;
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正文语种 eng
中图分类细胞生物学;
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Akt; B cells; Cell migration; CXCL13; FAK; Integrin-mediated adhesion; Marginal zone B cells; Pyk2; Sphingosine 1-phosphate;

机译：Akt;B细胞;细胞迁移;CXCL13;FAK;整合素介导的粘附;边缘区B细胞;Pyk2;鞘氨醇1-磷酸;

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1. 悬浮培养GLC-82肺肿瘤细胞积聚体与蛋白激酶FAK、AKT、ERK和SRC活化的关系 [J] . 方翼, 张星, 张积仁, 癌症（英文版） . 2005,第010期
2. Small molecule inhibitors of the Pyk2 and FAK kinases modulate chemoattractant-induced migration, adhesion and Akt activation in follicular and marginal zone B cells [J] . TseK.W.K., LinK.B.L., Dang-LawsonM., Cellular immunology . 2012,第1a2期

机译：Pyk2和FAK激酶的小分子抑制剂调节滤泡和边缘区B细胞中趋化因子诱导的迁移，粘附和Akt活化
3. A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl) -3, 5, 7-triaza-1-azoniatricyclo [3.3.1.1 3,7]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo [J] . GolubovskayaV.M., FigelS., HoB.T., Carcinogenesis . 2012,第5期

机译：一种靶向Y397位点的小分子粘着斑激酶（FAK）抑制剂：1-（2-羟乙基）-3,5,7-三氮杂-1-氮杂三环[3.3.1.1 3,7]癸烷;溴化物可有效抑制FAK自磷酸化活性并降低体内癌细胞的活力，克隆性和肿瘤生长
4. A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl) -3, 5, 7-triaza-1-azoniatricyclon [3.3.1.13,7]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicityn and tumor growth in vivo [J] . Carcinogenesis . 2012,第5期

机译：一种靶向Y397位点的小分子粘着斑激酶（FAK）抑制剂：1-（2-羟乙基）-3，5，5，7-三氮杂-1-氮杂三环烷[3.3.1.13,7]癸烷；溴化物可有效抑制FAK自磷酸化活性并降低体内癌细胞的活力，克隆形成性和肿瘤生长
5. Inhibition of HAS2 expression by siRIMA inhibits phosphorylation of focal adhesion kinase and migration in vascular smooth muscle cells [C] . M. Sussmann, K. Schror, J.W. Fische Nordrhein-Westfa?lische Akademie der Wissenschaften . 2005

机译：Sirima的Hase2表达的抑制抑制局灶性粘附激酶的磷酸化和血管平滑肌细胞中的迁移
6. FERM on one end, FAT on the other; when looking at the FAKs, a Pyk2 is worth a thousand words: X-ray crystal structures of the focal adhesion targeting and FERM domains of the tyrosine kinase Pyk2. [D] . Lulo, James Edmond. 2009

机译：FERM一端，FAT另一端；当查看FAK时，Pyk2值一千个字：酪氨酸激酶Pyk2的粘着斑靶向和FERM域的X射线晶体结构。
7. Induced Focal Adhesion Kinase (FAK) Expression in FAK-Null Cells Enhances Cell Spreading and Migration Requiring Both Auto- and Activation Loop Phosphorylation Sites and Inhibits Adhesion-Dependent Tyrosine Phosphorylation of Pyk2 [O] . James D. Owen, Paul J. Ruest, David W. Fry, 1999

机译：在FAK空细胞中诱导的局灶性粘附激酶（FAK）表达增强细胞的扩散和迁移需要自动和激活环磷酸化位点并抑制Pyk2的粘附依赖性酪氨酸磷酸化。
8. Induced Focal Adhesion Kinase (FAK) Expression in FAK-Null Cells Enhances Cell Spreading and Migration Requiring Both Auto- and Activation Loop Phosphorylation Sites and Inhibits Adhesion-Dependent Tyrosine Phosphorylation of Pyk2 [O] . Owen, James D., Ruest, Paul J., Fry, David W., 1999

机译：在FAK空细胞中诱导的局灶性粘附激酶（FAK）表达增强细胞的扩散和迁移，需要自动和激活环磷酸化位点，并抑制Pyk2的粘附依赖性酪氨酸磷酸化。

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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