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Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities
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Title: | Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities |
Authors: | Ibata, Makoto Browse this author | Iwasaki, Junko Browse this author | Fujioka, Yoichiro Browse this author | Nakagawa, Koji Browse this author →KAKEN DB | Darmanin, Stephanie Browse this author | Onozawa, Masahiro Browse this author →KAKEN DB | Hashimoto, Daigo Browse this author | Ohba, Yusuke Browse this author →KAKEN DB | Hatakeyama, Shigetsugu Browse this author →KAKEN DB | Teshima, Takanori Browse this author →KAKEN DB | Kondo, Takeshi Browse this author →KAKEN DB |
Keywords: | FIP1L1-PDGFRA | leukemogenesis | phosphorylation | PIAS1 | sumoylation |
Issue Date: | Feb-2017 |
Publisher: | Wiley |
Journal Title: | Cancer Science |
Volume: | 108 |
Issue: | 2 |
Start Page: | 200 |
End Page: | 207 |
Publisher DOI: | 10.1111/cas.13129 |
Abstract: | Fusion tyrosine kinases play a crucial role in the development of hematological malignancies. FIP1L1-PDGFRA is a leukemogenic fusion kinase that causes chronic eosinophilic leukemia. As a constitutively active kinase, FIP1L1-PDGFRA stimulates downstream signaling molecules, leading to cellular proliferation and the generation of an anti-apoptotic state. Contribution of the N-terminal FIP1L1 portion is necessary for FIP1L1-PDGFRA to exert its full transforming activity, but the underlying mechanisms have not been fully characterized. We identified PIAS1 as a FIP1L1-PDGFRA association molecule by yeast two-hybrid screening. Our analyses indicate that the FIP1L1 portion of FIP1L1-PDGFRA is required for efficient association with PIAS1. As a consequence of the association, FIP1L1-PDGFRA phosphorylates PIAS1. Moreover, the kinase activity of FIP1L1-PDGFRA stabilizes PIAS1. Therefore, PIAS1 is one of the downstream targets of FIP1L1-PDGFRA. Moreover, we found that PIAS1, as a SUMO E3 ligase, sumoylates and stabilizes FIP1L1-PDGFRA. In addition, suppression of PIAS1 activity by a knockdown experiment resulted in destabilization of FIP1L1-PDGFRA. Therefore, FIP1L1-PDGFRA and PIAS1 form a positive cross-talk through their enzymatic activities. Suppression of sumoylation by ginkgolic acid, a small molecule compound inhibiting a SUMO E1-activating enzyme, also destabilizes FIP1L1-PDGFRA, and while the tyrosine kinase inhibitor imatinib suppresses FIP1L1-PDGFRA-dependent cell growth, ginkgolic acid or siRNA of PIAS1 has a synergistic effect with imatinib. In conclusion, our results suggest that sumoylation by PIAS1 is a potential target in the treatment of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. |
Rights: | http://creativecommons.org/licenses/by-nc/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/65802 |
Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 近藤 健
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