Gil-Henn Hava, Destaing Olivier, Sims Natalie A, Aoki Kazuhiro, Alles Neil, Neff Lynn, Sanjay Archana, Bruzzaniti Angela, De Camilli Pietro, Baron Roland, Schlessinger Joseph
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06511, USA.
J Cell Biol. 2007 Sep 10;178(6):1053-64. doi: 10.1083/jcb.200701148.
The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2(-/-) mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.
蛋白酪氨酸激酶Pyk2在破骨细胞中高度表达，主要定位于足体。小鼠中Pyk2的缺失由于破骨细胞功能受损导致轻度骨质石化。Pyk2基因敲除的破骨细胞无法将足体簇转化为细胞周边的足体带；仅形成小的肌动蛋白环而非封闭带，导致骨吸收受损。此外，在Pyk2基因敲除的破骨细胞中，Rho活性增强，而微管乙酰化和稳定性显著降低。通过在Pyk2(-/-)小鼠破骨细胞中异位表达野生型或多种Pyk2突变体进行的拯救实验表明，Pyk2的FAT结构域对于足体带和封闭带的形成以及骨吸收至关重要。这些实验强调了Pyk2在微管依赖性足体组织、骨吸收和其他破骨细胞功能中的重要作用。
