RRC ID 49630
Author Ibata M, Iwasaki J, Fujioka Y, Nakagawa K, Darmanin S, Onozawa M, Hashimoto D, Ohba Y, Hatakeyama S, Teshima T, Kondo T.
Title Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities.
Journal Cancer Sci.
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.
Volume 108(2)
Pages 200-207
Published 2017-2
DOI 10.1111/cas.13129
PMID 27960034
PMC PMC5367148
MeSH Apoptosis Cell Nucleus / metabolism* HEK293 Cells Humans Hypereosinophilic Syndrome / drug therapy Hypereosinophilic Syndrome / metabolism Imatinib Mesylate / therapeutic use Immunoblotting Immunoprecipitation Oncogene Proteins, Fusion / chemistry Oncogene Proteins, Fusion / metabolism* Protein Inhibitors of Activated STAT / chemistry Protein Inhibitors of Activated STAT / metabolism* Protein Kinase Inhibitors / therapeutic use Protein-Tyrosine Kinases / metabolism Receptor, Platelet-Derived Growth Factor alpha / chemistry Receptor, Platelet-Derived Growth Factor alpha / metabolism* STAT1 Transcription Factor / chemistry STAT1 Transcription Factor / metabolism* Signal Transduction Sumoylation Transfection / methods mRNA Cleavage and Polyadenylation Factors / chemistry mRNA Cleavage and Polyadenylation Factors / metabolism*
IF 4.372
Resource
DNA material pFLAG-FIP1L1-PDGFRA-FL (RDB15460) pFLAG-FIP1L1-PDGFRA-KD (RDB15461) pFLAG-PDGFRA-C (RDB15462) pCGT-FIP1L1-PDGFRA-FL (RDB15463) pCGT-FIP1L1-PDGFRA-KD (RDB15464) pCGT-PDGFRAC (RDB15465).