ACTIVATION OF RHOA-VAV1 SIGNALING IN ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA
| Autor: | Terukazu Enami, Koji Izutsu, Koichi Ohshima, Philippe Gaulard, Naoya Nakamura, P. Gershon, Kenichi Yoshida, Kengo Takeuchi, Motoko Fujisawa, M. Kiryu, K. Fukumoto, Kosei Matsue, Seishi Ogawa, Mamiko Sakata-Yanagimoto, Takanori Teshima, Shigeru Chiba, Shoko Nishizawa, Hiroaki Miyoshi, S Tanzima, M. Muratani, Katsuya Fujimoto, Daisuke Komori |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Angioimmunoblastic T-cell lymphoma RHOA VAV1 GTP' medicine.medical_treatment DNA Mutational Analysis Receptors Antigen T-Cell medicine.disease_cause Lymphoma T-Cell 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Biomarkers Tumor medicine Humans Phosphorylation Proto-Oncogene Proteins c-vav Receptor Mutation NFATC Transcription Factors biology Chemistry T-cell receptor Hematology General Medicine medicine.disease 3. Good health 030104 developmental biology Cytokine Oncology Immunoblastic Lymphadenopathy 030220 oncology & carcinogenesis biology.protein Cancer research Cytokines Original Article Signal transduction rhoA GTP-Binding Protein Protein Binding Signal Transduction |
| Zdroj: | Leukemia |
| ISSN: | 0278-0232 |
| DOI: | 10.1002/hon.2437_44 |
| Popis: | Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), while none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was demonstrated also in VAV1-STAP2. Dasatinib, a multi-kinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phsopho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.Leukemia accepted article preview online, 23 August 2017. doi:10.1038/leu.2017.273. |
| Databáze: | OpenAIRE |
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