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

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

Research output: Contribution to journalArticle

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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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Signal Transducing Adaptor Proteins
Carcinogenesis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
B-Cell Lymphoma
STAT5 Transcription Factor

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Sekine, Y., Ikeda, O., Mizushima, A., Ueno, Y., Muromoto, R., Yoshimura, A., ... 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

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis. / Sekine, Y.; Ikeda, O.; Mizushima, A.; Ueno, Y.; Muromoto, R.; Yoshimura, Akihiko; Kanakura, Y.; Oritani, K.; Matsuda, T.

In: Oncogene, Vol. 31, No. 40, 04.10.2012, p. 4384-4396.

Research output: Contribution to journalArticle

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, vol. 31, no. 40, pp. 4384-4396. https://doi.org/10.1038/onc.2011.604
Sekine Y, Ikeda O, Mizushima A, Ueno Y, Muromoto R, Yoshimura A et al. STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis. Oncogene. 2012 Oct 4;31(40):4384-4396. https://doi.org/10.1038/onc.2011.604
Sekine, Y. ; Ikeda, O. ; Mizushima, A. ; Ueno, Y. ; Muromoto, R. ; Yoshimura, Akihiko ; Kanakura, Y. ; Oritani, K. ; Matsuda, T. / STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis. In: Oncogene. 2012 ; Vol. 31, No. 40. pp. 4384-4396.
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AU - Yoshimura, Akihiko

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AB - 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.

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