Center for Biomedical Research, Population Council, 1230 York Avenue, New York, NY 10065, USA.
Int J Biochem Cell Biol. 2011 Apr;43(4):651-65. doi: 10.1016/j.biocel.2011.01.008. Epub 2011 Jan 21.
During spermatogenesis, extensive junction restructuring takes place at the blood-testis barrier (BTB) and the Sertoli cell-spermatid interface known as the apical ectoplasmic specialization (apical ES, a testis-specific adherens junction) in the seminiferous epithelium. However, the mechanism(s) that regulates these critical events in the testis remains unknown. Based on the current concept in the field, changes in the phosphorylation status of integral membrane proteins at these sites can induce alterations in protein endocytosis and recycling, causing junction restructuring. Herein, c-Yes, a non-receptor protein tyrosine kinase, was found to express abundantly at the BTB and apical ES stage-specifically, coinciding with junction restructuring events at these sites during the seminiferous epithelial cycle of spermatogenesis. c-Yes also structurally associated with adhesion proteins at the BTB (e.g., occludin and N-cadherin) and the apical ES (e.g., β1-integrin, laminins β3 and γ3), possibly to regulate phosphorylation status of proteins at these sites. SU6656, a selective c-Yes inhibitor, was shown to perturb the Sertoli cell tight junction-permeability barrier in vitro, which is mediated by changes in the distribution of occludin and N-cadherin at the cell-cell interface, moving from cell surface to cytosol, thereby destabilizing the tight junction-barrier. However, this disruptive effect of SU6656 on the barrier was blocked by testosterone. Furthermore, c-Yes is crucial to maintain the actin filament network in Sertoli cells since a blockade of c-Yes by SU6656 induced actin filament disorganization. In summary, c-Yes regulates BTB and apical ES integrity by maintaining proper distribution of integral membrane proteins and actin filament organization at these sites.
在精子发生过程中，广泛的连接重建发生在血睾屏障（BTB）和支持细胞-精子界面，称为顶外侧细胞外特化（顶 ES，一种睾丸特异性粘着连接）在生精上皮中。然而，调节睾丸中这些关键事件的机制尚不清楚。根据目前该领域的概念，这些部位的整合膜蛋白磷酸化状态的变化可以诱导蛋白内吞和回收的改变，导致连接重建。在此，c-Yes，一种非受体蛋白酪氨酸激酶，在 BTB 和顶 ES 部位特异性地大量表达，与精子发生过程中生精上皮周期中这些部位的连接重建事件相一致。c-Yes 还与 BTB 处的粘附蛋白（如occludin 和 N-cadherin）和顶 ES 处的粘附蛋白（如β1-整合素、层粘连蛋白β3 和γ3）结构相关，可能调节这些部位蛋白的磷酸化状态。SU6656，一种选择性 c-Yes 抑制剂，被证明在体外扰乱了支持细胞紧密连接通透性屏障，这是通过 occludin 和 N-cadherin 在细胞-细胞界面的分布变化介导的，从细胞膜表面转移到细胞质中，从而破坏了紧密连接屏障。然而，睾酮阻断了 SU6656 对屏障的这种破坏作用。此外，c-Yes 对维持支持细胞中的肌动蛋白丝网络至关重要，因为 SU6656 阻断 c-Yes 会诱导肌动蛋白丝的紊乱。总之，c-Yes 通过维持这些部位的整合膜蛋白和肌动蛋白丝组织的适当分布来调节 BTB 和顶 ES 的完整性。
