title: Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities.
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.
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ibata
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Iwasaki
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Fujioka
authors.affiliation: Department of Laboratory of Pathophysiology and Therapeutics, Hokkaido University Faculty of Pharmaceutical Sciences, Sapporo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Darmanin
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Onozawa
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Hashimoto
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy / Q000378:metabolism; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D015151:Immunoblotting; D047468:Immunoprecipitation; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000737:chemistry / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000737:chemistry / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D014162:Transfection / Q000379:methods; D039221:mRNA Cleavage and Polyadenylation Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; D050828:Protein Inhibitors of Activated STAT; D047428:Protein Kinase Inhibitors; D050794:STAT1 Transcription Factor; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: FIP1L1-PDGFRA; PIAS1; leukemogenesis; phosphorylation; sumoylation