STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

Y. Sekine, O. Ikeda, A. Mizushima, Y. Ueno, R. Muromoto, A. Yoshimura, Y. Kanakura, K. Oritani, T. Matsuda

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Abstract

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.

Original languageEnglish
Pages (from-to)4384-4396
Number of pages13
JournalOncogene
Volume31
Issue number40
DOIs
Publication statusPublished - 2012 Oct 4

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Keywords

  • BCR-ABL
  • chemokine
  • chronic myeloid leukemia
  • signal-transducing adaptor protein-2
  • tumorigenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Sekine, Y., Ikeda, O., Mizushima, A., Ueno, Y., Muromoto, R., Yoshimura, A., Kanakura, Y., Oritani, K., & Matsuda, T. (2012). STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis. Oncogene, 31(40), 4384-4396. https://doi.org/10.1038/onc.2011.604