Duning Kerstin, Schurek Eva-Maria, Schlüter Marc, Bayer Michael, Reinhardt Hans-Christian, Schwab Albrecht, Schaefer Liliana, Benzing Thomas, Schermer Bernhard, Saleem Moin A, Huber Tobias B, Bachmann Sebastian, Kremerskothen Joachim, Weide Thomas, Pavenstädt Hermann
Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster, Münster, Germany.
J Am Soc Nephrol. 2008 Oct;19(10):1891-903. doi: 10.1681/ASN.2007080916. Epub 2008 Jul 2.
Asymmetric delivery and distribution of macromolecules are essential for cell polarity and for cellular functions such as differentiation, division, and signaling. Injury of podocytes, which are polarized epithelial cells, changes the dynamics of the actin meshwork, resulting in foot process retraction and proteinuria. Although the spatiotemporal control of specific protein-protein interactions is crucial for the establishment of cell polarity, the mechanisms controlling polarity-dependent differentiation and division are incompletely understood. In this study, yeast two-hybrid screens were performed using a podocyte cDNA library and the polarity protein PATJ as bait. The protein KIBRA was identified as an interaction partner of PATJ and was localized to podocytes, tubular structures, and collecting ducts. The last four amino acids of KIBRA mediated binding to the eighth PDZ domain of PATJ. In addition, KIBRA directly bound to synaptopodin, an essential organizer of the podocyte cytoskeleton. Stable knockdown of KIBRA in immortalized podocytes impaired directed cell migration, suggesting that KIBRA modulates the motility of podocytes by linking polarity proteins and cytoskeleton-associated protein complexes.
大分子的不对称传递和分布对于细胞极性以及诸如分化、分裂和信号传导等细胞功能至关重要。足细胞作为极化上皮细胞，其损伤会改变肌动蛋白网络的动力学，导致足突回缩和蛋白尿。尽管特定蛋白质 - 蛋白质相互作用的时空控制对于细胞极性的建立至关重要，但控制极性依赖性分化和分裂的机制仍未完全了解。在本研究中，以足细胞cDNA文库和极性蛋白PATJ为诱饵进行酵母双杂交筛选。蛋白质KIBRA被鉴定为PATJ的相互作用伙伴，并定位于足细胞、肾小管结构和集合管。KIBRA的最后四个氨基酸介导了与PATJ的第八个PDZ结构域的结合。此外，KIBRA直接与突触足蛋白结合，突触足蛋白是足细胞细胞骨架的重要组织者。在永生化足细胞中稳定敲低KIBRA会损害定向细胞迁移，这表明KIBRA通过连接极性蛋白和细胞骨架相关蛋白复合物来调节足细胞的运动性。
