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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)

Submitter: 近藤 健

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