STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis
| Autor: | Y Ueno, Osamu Ikeda, Ryuta Muromoto, Yuzuru Kanakura, Yuichi Sekine, Akihiko Yoshimura, Akihiro Mizushima, Tadashi Matsuda, Kenji Oritani |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Fusion Proteins bcr-abl Mice Downregulation and upregulation chronic myeloid leukemia Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Genetics Animals Humans Phosphorylation Extracellular Signal-Regulated MAP Kinases BCR-ABL neoplasms Molecular Biology signal-transducing adaptor protein-2 STAT5 Adaptor Proteins Signal Transducing ABL biology chemokine breakpoint cluster region Signal transducing adaptor protein Phosphoproteins tumorigenesis Cell Transformation Neoplastic Tumor progression biology.protein Cancer research Receptors Chemokine Protein Binding Proto-oncogene tyrosine-protein kinase Src K562 cells |
| Zdroj: | Oncogene. 31:4384-4396 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2011.604 |
| Popis: | In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal-transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn upregulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK (extracellular-signal-regulated kinase), STAT5 (signal transducer and activator of transcription 5), BCL-xL (B-cell lymphoma-extra large) and BCL-2(B-cell lymphoma 2). In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Furthermore, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones. |
| Databáze: | OpenAIRE |
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