FKBP51 regulates cell motility and invasion via RhoA signaling.
FKBP51 regulates cell motility and invasion via RhoA signaling.
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DOI：
10.1111/cas.13153
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发表时间：
2017-03
期刊：
影响因子：
5.7
通讯作者：
Nakanishi A
中科院分区：
文献类型：
--
作者：
Takaoka M;Ito S;Miki Y;Nakanishi A
FK506结合蛋白51 （FKBP51）是亲免疫蛋白家族的一员，参与多种信号通路、肿瘤发生和化疗耐药。FKBP51的表达与黑色素瘤和前列腺癌的转移潜力相关。然而，FKBP51的功能，特别是涉及细胞运动和侵袭的调节，尚不完全清楚。我们利用免疫沉淀和质谱法发现了FKBP51的两个新的相互作用伴侣蛋白，即肝癌1中缺失（DLC1）和肝癌2中缺失（DLC2）。DLC1和DLC2是Rho GTPase激活蛋白，在各种癌症中经常下调。接下来，我们证明了FKBP51的过表达通过上调RhoA活性和增强Rho‐ROCK信号传导来增强细胞运动和U2OS细胞的侵袭。此外，FKBP51缺失的细胞表现出肌动蛋白丝的皮质分布，细胞运动性和侵袭性下降。与这种表型一致，FKBP51缺失导致RhoA活性下调。综上所述，我们的研究结果表明FKBP51通过促进RhoA和ROCK激活来积极控制细胞运动；因此，我们揭示了FKBP51在细胞骨架重排和细胞迁移和侵袭中的新作用。
FK506 binding protein 51 (FKBP51), a member of the immunophilin family, is involved in multiple signaling pathways, tumorigenesis, and chemoresistance. FKBP51 expression correlates with metastatic potential in melanoma and prostate cancer. However, the functions of FKBP51, particularly involving the regulation of cell motility and invasion, are not fully understood. We discovered two novel interacting partner proteins of FKBP51, i.e., deleted in liver cancer 1 (DLC1) and deleted in liver cancer 2 (DLC2), using immunoprecipitation and mass spectrometry. DLC1 and DLC2 are Rho GTPase‐activating proteins that are frequently downregulated in various cancers. Next, we demonstrated that overexpression of FKBP51 enhances cell motility and invasion of U2OS cells via upregulation of RhoA activity and enhanced Rho‐ROCK signaling. Moreover, FKBP51‐depleted cells displayed a cortical distribution of actin filaments and decreased cell motility and invasion. Consistent with this phenotype, FKBP51 depletion caused a downregulation of RhoA activity. Considered together, our results demonstrate that FKBP51 positively controls cell motility by promoting RhoA and ROCK activation; thus, we have revealed a novel role for FKBP51 in cytoskeletal rearrangement and cell migration and invasion.