The role of SWAP-70 in mast cell adhesion, migration and F-actin cytokeletal rearrangements

SWAP-70 在肥大细胞粘附、迁移和 F-肌动蛋白细胞骨架重排中的作用

• 批准号: 124375780
• 负责人: Professor Dr. Rolf Jessberger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/124375780?language=en
• 关键词: role; SWAP; 70; mast; cell

Migration and adhesion of mast cells (MCs) is essential for their function and must be properly regulated, F-actin dynamics and adhesion receptors are to be controlled. Earlier we demonstrated the F-actin binding protein SWAP-70 as an important modulator of MC migration and adhesion. In the 1st funding period we identified a novel interaction and two novel mechanisms with which SWAP-70 controls F-actin rearrangements: (i) direct physial interaction with the F-actin severing protein cofilin and restriction of its activity, and (ii) bundling and stabilization of actin filaments by SWAP-70. Also, we further characterized SWAP-70 control of integrins and showed their physical interaction with SWAP-70. Furthermore, we accumulated evidence for a hitherto largely unknown function of cadherins, i.e. E-Cdh, in MCs and a MCspecific E-Cdh deficient mouse strain is being generated. Indications now emerged for partially overlapping functions of SWAP-70 and its only closely related protein, DEF6. The Swap-70-/- Def6-/- strain was generated and its MC will now be analyzed in vivo and in vitro. In addition, a MC-specific SWAP-70 deficient mouse strain was generated based on Mcpt5-Cre expression in Swap-70floxed mice. This new strain will eliminate bystander effects of other SWAP-70 deficient cell types. Together, in the 2nd funding period, we will further analyze control of integrins by SWAP-70, will explore the newly identified SWAP-70 control of cofilin, will determine the function of E-Cdh in MCs and the role of SWAP-70 therein, and will include analysis of DEF6 and its relationship to SWAP-70 in MCs. With this program we expect to contribute significantly to our understanding of central pathways and mechanisms that govern MC migration and adhesion.

肥大细胞 (MC) 的迁移和粘附对其功能至关重要，必须对其进行适当调节，F-肌动蛋白动力学和粘附受体也需要控制。早些时候，我们证明了 F-肌动蛋白结合蛋白 SWAP-70 作为 MC 迁移和粘附的重要调节剂。在第一个资助期，我们发现了 SWAP-70 控制 F-肌动蛋白重排的一种新的相互作用和两种新机制：(i) 与 F-肌动蛋白切断蛋白丝切蛋白的直接物理相互作用并限制其活性，以及​​ (ii) SWAP-70 对肌动蛋白丝的捆绑和稳定。此外，我们还进一步表征了 SWAP-70 对整合素的控制，并展示了它们与 SWAP-70 的物理相互作用。此外，我们积累了迄今为止很大程度上未知的钙粘蛋白（即 E-Cdh）在 MC 中的功能的证据，并且正在产生 MC 特异性 E-Cdh 缺陷小鼠品系。现在出现了 SWAP-70 及其唯一密切相关的蛋白质 DEF6 部分重叠功能的迹象。 Swap-70-/- Def6-/- 菌株已生成，现在将对其 MC 进行体内和体外分析。此外，根据 Swap-70floxed 小鼠中的 Mcpt5-Cre 表达，生成了 MC 特异性 SWAP-70 缺陷小鼠品系。这种新菌株将消除其他 SWAP-70 缺陷细胞类型的旁观者效应。在第二个资助期间，我们将进一步分析 SWAP-70 对整合素的控制，探索新发现的 SWAP-70 对 cofilin 的控制，确定 E-Cdh 在 MC 中的功能以及 SWAP-70 在其中的作用，并将包括对 DEF6 及其与 MC 中 SWAP-70 的关系的分析。通过这个项目，我们希望能够为我们对控制 MC 迁移和粘附的中心途径和机制的理解做出重大贡献。