Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities

Ibata, Makoto; Iwasaki, Junko; Fujioka, Yoichiro; Nakagawa, Koji; Darmanin, Stephanie; Onozawa, Masahiro; Hashimoto, Daigo; Ohba, Yusuke; Hatakeyama, Shigetsugu; Teshima, Takanori; Kondo, Takeshi

Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities

Ibata, Makoto; Iwasaki, Junko; Fujioka, Yoichiro et al.

Cancer Science, 2017, 108(2), 200-207

Permalink : https://hdl.handle.net/2115/65802

このアイテムのアクセス数:1,098件（2026-08-13 19:22 集計）

閲覧可能ファイル

ファイル	フォーマット	サイズ	閲覧回数	説明
Ibata_et_al-2017-Cancer_Science	pdf	906 KB	567

論文情報

ファイル出力 EndNote Basic出力 Mendeley出力

アクセス権	open access
URI	https://hdl.handle.net/2115/65802
タイトル	Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities
著者	Ibata, Makoto ; Iwasaki, Junko ; Fujioka, Yoichiro ; Nakagawa, Koji ; Darmanin, Stephanie ; Onozawa, Masahiro ; Hashimoto, Daigo ; Ohba, Yusuke ; Hatakeyama, Shigetsugu ; Teshima, Takanori ; Kondo, Takeshi
著者名 Ibata, Makoto
著者名 Iwasaki, Junko
著者名 Fujioka, Yoichiro
e-Rad_Researcher 80360949 著者名 Nakagawa, Koji
著者名 Darmanin, Stephanie
e-Rad_Researcher 70455632 著者名 Onozawa, Masahiro
著者名 Hashimoto, Daigo
e-Rad_Researcher 30333503 著者名 Ohba, Yusuke
e-Rad_Researcher 70294973 著者名 Hatakeyama, Shigetsugu
e-Rad_Researcher 40284096 著者名 Teshima, Takanori
e-Rad_Researcher 70333606 著者名 Kondo, Takeshi
言語	英語
キーワード	FIP1L1-PDGFRA
	leukemogenesis
	phosphorylation
	PIAS1
	sumoylation
発行日	2017-02
出版者	Wiley
収録物名	Cancer Science
巻(号)	108(2)
ページ	200-207
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	Creative Commons Attribution-NonCommercial 4.0 International
PISSN	1347-9032
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1111/cas.13129