Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements
Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements
复制标题
DOI：
10.1096/fj.10-158212
复制
发表时间：
2010-12-01
期刊：
影响因子：
4.8
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
--
作者：
Takegahara, Noriko;Kang, Sujin;Kumanogoh, Atsushi
Podosomes是最近重新发现的高度动态的富含肌动蛋白的结构和功能模块，与周围的底物形成紧密接触。它们在控制高度运动细胞（包括淋巴细胞、巨噬细胞、树突细胞和破骨细胞）的迁移、组织侵袭和基质重塑中发挥作用。在破骨细胞中，podosomes的压实诱导形成紧密的粘附接触，密封区，其限定了专门用于骨吸收的亚骨环境。整合素和Rho家族小GTP酶是足体重排的关键调节因子。然而，它仍然有待确定如何激活的整合素和Rho家族的GTP酶调节破骨细胞的podosome重排。在这里，我们证明了一个关键的作用，为FERM结构域的鸟嘌呤核苷酸交换因子（GEF），FARP 2，在破骨细胞的podosome重排和再吸收活动。我们通过活细胞成像和生化测定确定FARP 2是GTP结合的Rac 1局部激活成podosome环样结构所必需的。此外，FARP 2与破骨细胞生成过程中的整合素β 3活性相关。此外，与野生型破骨细胞（对照）相比，FARP 2缺陷导致多核破骨细胞和吸收陷窝的形成减少。总的来说，我们的研究结果揭示了FARP 2在破骨细胞发生中调节Rac 1和整联蛋白β 3在整个足体重排中的不可或缺的作用。Takegahara，N.，康，S.，Nojima，S.，Takamatsu，H.，Okuno，T.，菊谷，H.，Toyofuku，T.，Kumanogoh，A.鸟嘌呤核苷酸交换因子FARP 2在破骨细胞足体重排中的重要作用FASEB J.24，4782-4792（2010）。www.fasebj.org
Podosomes are recently rediscovered highly dynamic actin-rich structural and functional modules that form close contact with the surrounding substrate. They play a role in the control of migration, tissue invasion, and matrix remodeling of highly motile cells, including lymphocytes, macrophages, dendritic cells, and osteoclasts. In osteoclasts, the compaction of podosomes induces the formation of a tight adhesive contact, the sealing zone, which defines a subosteoclastic environment specialized for bone resorption. Integrins and the Rho family small GTPases are key regulators of podosome rearrangements. However, it remains to be determined how the activation of integrins and Rho family GTPases is regulated during osteoclast podosome rearrangements. Here, we demonstrate a crucial role for the FERM domain-containing guanine nucleotide exchange factor (GEF), FARP2, in osteoclast podosome rearrangements and resorbing activity. We determine by live cell imaging and biochemical assays that FARP2 is required for localized activation of GTP-bound Rac1 into podosome-ring like structures. In addition, FARP2 is relevant to integrin beta 3 activity during osteoclastogenesis. Furthermore, FARP2 deficiency results in reduced formation of multinucleated osteoclasts and resorption pits compared to wild-type osteoclasts (controls). Collectively, our findings reveal an integral role of FARP2 for regulation of Rac1 and integrin beta 3 throughout podosome rearrangement in osteoclastogenesis.-Takegahara, N., Kang, S., Nojima, S., Takamatsu, H., Okuno, T., Kikutani, H., Toyofuku, T., Kumanogoh, A. Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements. FASEB J. 24, 4782-4792 (2010). www.fasebj.org