Rho GTPase regulation in trophoblasts by c-Jun N-terminalkinase signaling

c-Jun N 末端激酶信号传导对滋养细胞中 Rho GTPase 的调节

基本信息

  • 批准号:
    10749994
  • 负责人:
  • 金额:
    $ 4.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Placental development is critical in the early stages of pregnancy, as dysregulation of this process can lead to intrauterine growth restriction of the fetus, preeclampsia, and miscarriage. A fundamental step in placental development is the invasion of extravillous trophoblast cells into the endometrium of the uterus. A key mediator of the invasive trophoblast phenotype is cytoskeletal remodeling driven by the activity of the small GTPase Rho. Dynamic changes in the cytoskeleton are indispensable for initiating cell polarity and forming cell protrusions and adhesions that drive cell migration, and the tightly coordinated regulation of these changes is critical for successful placental development. However, the specific signaling mechanisms that regulate Rho GTPase cytoskeletal remodeling during trophoblast invasion remain unclear. Previously published data have suggested that the c-Jun-N-terminal kinase (JNK) subfamily of mitogen-activated protein kinases (MAPKs) may be involved in trophoblast invasion, however the mechanism by which it accomplishes this is not well understood. Recent screens from our lab have identified the Rho GTPase activating proteins (Rho GAPs) SYDE1 and SYDE2 as novel JNK substrates based on kinase-substrate docking interactions. Existing literature indicate roles of SYDE1 and SYDE2 in migration in trophoblasts and cytoskeletal remodeling. It is therefore likely that SYDE1 and/or SYDE2 may be involved in a JNK signaling axis that regulates Rho GTPase cytoskeletal rearrangement and migration during trophoblast invasion. The objective of this proposal is to elucidate how JNK modulates SYDE1 and SYDE2 to control migration and invasion of trophoblasts. This proposal will determine the functional consequences of JNK-mediated regulation of SYDE1 and SYDE2 in trophoblasts by examining the effects on cell morphology, cytoskeletal organization, and migration in human trophoblast cells harboring SYDE1 or SYDE2 deletion or overexpression. Placental tissue samples will also be analyzed to examine clinical relevance of JNK signaling through these proteins. GTPase biosensor assays will be used to determine whether JNK phosphorylation of SYDE1 and SYDE2 positively regulates their activity as Rho GAPs. In vitro GTPase assays will determine whether this mechanism is accomplished by affecting GAP enzymatic activity. In order to establish whether any observed effects are dependent on JNK phosphorylation, JNK inhibitors and docking-site mutant SYDE1 and SYDE2 will be used to ablate JNK-specific phosphorylation. Ultimately, identifying JNK and small GTPase regulators as a key molecular players in trophoblast signaling, as well as understanding the mechanisms by which they act, will allow them to be explored as molecular targets to treat severe pregnancy complications related to aberrant trophoblast migration.
项目摘要 胎盘发育在妊娠早期至关重要,因为这一过程的失调可导致 胎儿宫内生长受限、先兆子痫和流产。胎盘发育的一个基本步骤 发育是绒毛外滋养层细胞侵入子宫内膜。关键调解人 侵袭性滋养层细胞表型的一个重要特征是由小G T β Rho的活性驱动的细胞骨架重塑。 细胞骨架的动态变化对于启动细胞极性和形成细胞突起是必不可少的 以及驱动细胞迁移的粘附,这些变化的紧密协调调节对于 成功的胎盘发育。然而,调节Rho GT3的特定信号传导机制 滋养层细胞侵袭过程中的细胞骨架重塑仍不清楚。此前公布的数据显示, 提示丝裂原活化蛋白激酶(MAPK)的c-Jun-N-末端激酶(JNK)亚家族可能 参与滋养层侵入,然而其实现这一点的机制还不清楚。 我们实验室最近的筛选已经鉴定了Rho GT3激活蛋白(Rho GAP)SYDE 1和SYDE 2 作为基于激酶-底物对接相互作用的新型JNK底物。现有文献表明, SYDE 1和SYDE 2在滋养细胞迁移和细胞骨架重塑中的作用因此,SYDE 1可能 和/或SYDE 2可能参与调节Rho GT3细胞骨架重排的JNK信号传导轴 以及滋养层侵入时的迁移。本提案的目的是阐明JNK如何调节 SYDE 1和SYDE 2控制滋养细胞的迁移和侵袭。该提案将决定 JNK介导的滋养层SYDE 1和SYDE 2调节的功能后果, 对携带SYDE 1的人滋养层细胞的细胞形态、细胞骨架组织和迁移的影响 或SYDE 2缺失或过表达。胎盘组织样本也将进行分析,以检查临床 JNK信号通过这些蛋白质的相关性。将使用GT3生物传感器测定来确定是否 SYDE 1和SYDE 2的JNK磷酸化正调节它们作为Rho GAP的活性。体外GT3 测定将确定该机制是否通过影响GAP酶活性来实现。为了 确定任何观察到的效应是否依赖于JNK磷酸化、JNK抑制剂和对接位点 突变体SYDE 1和SYDE 2将用于消除JNK特异性磷酸化。最终,识别JNK和 小GT3调节因子作为滋养层信号传导的关键分子参与者,以及了解 它们的作用机制将使它们成为治疗重度妊娠的分子靶点 异常滋养层细胞迁移相关的并发症。

项目成果

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