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FKBP51 regulates cell motility and invasion via RhoA signaling.

ABSTRACT: 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.

SUBMITTER: Takaoka M

PROVIDER: S-EPMC5378274 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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FKBP51 regulates cell motility and invasion via RhoA signaling.

Takaoka Miho M Ito Shun S Miki Yoshio Y Nakanishi Akira A

Cancer science 20170301 3

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 ...[more]

PMID: 28032931

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Project description:Abstract Background Melatonin (MEL), an endogenous hormone, has been widely investigated in neurological diseases. Microglia (MG), a resident immunocyte localizing in central nervous system is reported to play important functions in the animal model of temporal lobe epilepsy (TLE). Some evidence showed that MEL influenced activation of MG, but the detailed model of action that MEL plays in remains uncertain. Methods In this study, we established a model of TLE in mice by stereotactic injection of kainic acid (KA). We treated the mice with MEL. Lipopolysaccharide, ROCK2‐knockdown (ROCK‐KD) and ‐overexpression (ROCK‐OE) of lentivirus‐treated cells were used in cell experiments to simulate an in vitro inflammatory model. Results The results of electrophysiological tests showed that MEL reduced frequency and severity of seizure. The results of behavioral tests indicated MEL improved cognition, learning, and memory ability. Histological evidences demonstrated a significant reduction of neuronal death in the hippocampus. In vivo study showed that MEL changed the polarization status of MG from a proinflammatory M1 phenotype to an anti‐inflammatory M2 phenotype by inversely regulating the RhoA/ROCK signaling pathway. In cytological study, we found that MEL had a significant protective effect in LPS‐treated BV‐2 cells and ROCK‐KD cells, while the protective effect of MEL was significantly attenuated in ROCK‐OE cells. Conclusion MEL played an antiepileptic role in the KA‐induced TLE modeling mice both in behavioral and histological levels, and changed MG polarization status by regulating the RhoA/ROCK signaling pathway. 1. Melatonin (MEL) reduces frequency and severity of seizure. 2. MEL regulates the ROCK2 signaling pathway rather than ROCK1 to promote microglial polarization toward an anti‐inflammatory direction. 3. RhoA/ROCK2 signaling pathway might be a potential mechanism in the status epilepticus modeling mice. Highlights • Melatonin (MEL) reduces frequency and severity of seizure.• MEL regulates the ROCK2 signaling pathway rather than ROCK1 to promote microglial polarization toward an anti‐inflammatory direction.• RhoA/ROCK2 signaling pathway may be important in the temporal lobe epilepsy modeling mice.

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FKBP51 regulates cell motility and invasion via RhoA signaling.

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FKBP51 regulates cell motility and invasion via RhoA signaling.

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