Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 31, pages 4384–4396 (2012)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Brehme M, Hantschel O, Colinge J, Kaupe I, Planyavsky M, Kocher T et al. (2009). Charting the molecular network of the drug target Bcr-Abl. Proc Natl Acad Sci USA 106: 7414–7419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruennert D, Czibere A, Bruns I, Kronenwett R, Gattermann N, Haas R et al. (2009). Early in vivo changes of the transcriptome in Philadelphia chromosome-positive CD34+ cells from patients with chronic myelogenous leukaemia following imatinib therapy. Leukemia 23: 983–985.

    Article  CAS  PubMed  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.

    Article  CAS  PubMed  Google Scholar 

  • Chang YC, Tien SC, Tien HF, Zhang H, Bokoch GM, Chang ZF . (2009). p210(Bcr-Abl) desensitizes Cdc42 GTPase signaling for SDF-1alpha-directed migration in chronic myeloid leukemia cells. Oncogene 28: 4105–4115.

    Article  CAS  PubMed  Google Scholar 

  • Chu S, Li L, Singh H, Bhatia R . (2007). BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. Cancer Res 67: 7045–7053.

    Article  CAS  PubMed  Google Scholar 

  • Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW . (2003). Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 101: 4611–4614.

    Article  CAS  PubMed  Google Scholar 

  • Cortes J, Jabbour E, Kantarjian H, Yin CC, Shan J, O'Brien S et al. (2007). Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood 110: 4005–4011.

    Article  CAS  PubMed  Google Scholar 

  • Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE . (2005). hOCT 1 and resistance to imatinib. Blood 106: 1133–1134; author reply 1134.

    Article  CAS  PubMed  Google Scholar 

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231–241.

    Article  CAS  PubMed  Google Scholar 

  • del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . (1997). Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278: 687–689.

    Article  CAS  PubMed  Google Scholar 

  • Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. (2003). BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101: 690–698.

    Article  CAS  PubMed  Google Scholar 

  • Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S et al. (2003a). Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9: 625–632.

    CAS  PubMed  Google Scholar 

  • Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L . (2003b). Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 4: 75–85.

    Article  PubMed  Google Scholar 

  • Geay JF, Buet D, Zhang Y, Foudi A, Jarrier P, Berthebaud M et al. (2005). p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression. Cancer Res 65: 2676–2683.

    Article  CAS  PubMed  Google Scholar 

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. (2001). Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293: 876–880.

    Article  CAS  PubMed  Google Scholar 

  • Hochhaus A, La Rosee P . (2004). Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 18: 1321–1331.

    Article  CAS  PubMed  Google Scholar 

  • Hoelbl A, Kovacic B, Kerenyi MA, Simma O, Warsch W, Cui Y et al. (2006). Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation. Blood 107: 4898–4906.

    Article  CAS  PubMed  Google Scholar 

  • Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J et al. (2006). Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108: 28–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda O, Mizushima A, Sekine Y, Yamamoto C, Muromoto R, Nanbo A et al. (2011). Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells. Cancer Sci 102: 756–761.

    Article  CAS  PubMed  Google Scholar 

  • Jin L, Tabe Y, Konoplev S, Xu Y, Leysath CE, Lu H et al. (2008). CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells. Mol Cancer Ther 7: 48–58.

    Article  CAS  PubMed  Google Scholar 

  • le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G et al. (2000). Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 95: 1758–1766.

    CAS  PubMed  Google Scholar 

  • Lowenberg B . (2003). Minimal residual disease in chronic myeloid leukemia. N Engl J Med 349: 1399–1401.

    Article  PubMed  Google Scholar 

  • Ma Q, Jones D, Springer TA . (1999). The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10: 463–471.

    Article  CAS  PubMed  Google Scholar 

  • Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM et al. (2000). Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 96: 1070–1079.

    CAS  PubMed  Google Scholar 

  • Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F et al. (2010). Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11: 1029–1035.

    Article  CAS  PubMed  Google Scholar 

  • Mburu YK, Wang J, Wood MA, Walker WH, Ferris RL . (2006). CCR7 mediates inflammation-associated tumor progression. Immunol Res 36: 61–72.

    Article  CAS  PubMed  Google Scholar 

  • Minoguchi M, Minoguchi S, Aki D, Joo A, Yamamoto T, Yumioka T et al. (2003). STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif. J Biol Chem 278: 11182–11189.

    Article  CAS  PubMed  Google Scholar 

  • Mitchell PJ, Sara EA, Crompton MR . (2000). A novel adaptor-like protein which is a substrate for the non-receptor tyrosine kinase, BRK. Oncogene 19: 4273–4282.

    Article  CAS  PubMed  Google Scholar 

  • O'Hare T, Eide CA, Deininger MW . (2007). Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110: 2242–2249.

    Article  CAS  PubMed  Google Scholar 

  • Pap M, Cooper GM . (1998). Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 273: 19929–19932.

    Article  CAS  PubMed  Google Scholar 

  • Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T et al. (1999). Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283: 845–848.

    Article  CAS  PubMed  Google Scholar 

  • Pendergast AM, Muller AJ, Havlik MH, Maru Y, Witte ON . (1991). BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner. Cell 66: 161–171.

    Article  CAS  PubMed  Google Scholar 

  • Ptasznik A, Nakata Y, Kalota A, Emerson SG, Gewirtz AM . (2004). Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells. Nat Med 10: 1187–1189.

    Article  CAS  PubMed  Google Scholar 

  • Quintas-Cardama A, Cortes J . (2009). Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113: 1619–1630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren R . (2005). Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5: 172–183.

    Article  CAS  PubMed  Google Scholar 

  • Salgia R, Quackenbush E, Lin J, Souchkova N, Sattler M, Ewaniuk DS et al. (1999). The BCR/ABL oncogene alters the chemotactic response to stromal-derived factor-1alpha. Blood 94: 4233–4246.

    CAS  PubMed  Google Scholar 

  • Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E et al. (1996). The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3′ kinase pathway. Oncogene 12: 839–846.

    CAS  PubMed  Google Scholar 

  • Sekine Y, Ikeda O, Tsuji S, Yamamoto C, Muromoto R, Nanbo A et al. (2009a). Signal-transducing adaptor protein-2 regulates stromal cell-derived factor-1 alpha-induced chemotaxis in T cells. J Immunol 183: 7966–7974.

    Article  CAS  PubMed  Google Scholar 

  • Sekine Y, Tsuji S, Ikeda O, Kakisaka M, Sugiyama K, Yoshimura A et al. (2007a). Leukemia inhibitory factor-induced phosphorylation of STAP-2 on tyrosine-250 is involved in its STAT3-enhancing activity. Biochem Biophys Res Commun 356: 517–522.

    Article  CAS  PubMed  Google Scholar 

  • Sekine Y, Tsuji S, Ikeda O, Sugiyma K, Oritani K, Shimoda K et al. (2007b). Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase. J Immunol 179: 2397–2407.

    Article  CAS  PubMed  Google Scholar 

  • Sekine Y, Yamamoto C, Ikeda O, Muromoto R, Nanbo A, Oritani K et al. (2009b). The protein content of an adaptor protein, STAP-2 is controlled by E3 ubiquitin ligase Cbl. Biochem Biophys Res Commun 384: 187–192.

    Article  CAS  PubMed  Google Scholar 

  • Sekine Y, Yamamoto T, Yumioka T, Sugiyama K, Tsuji S, Oritani K et al. (2005). Physical and functional interactions between STAP-2/BKS and STAT5. J Biol Chem 280: 8188–8196.

    Article  CAS  PubMed  Google Scholar 

  • Sekine Y, Yumioka T, Yamamoto T, Muromoto R, Imoto S, Sugiyma K et al. (2006). Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages. J Immunol 176: 380–389.

    Article  CAS  PubMed  Google Scholar 

  • Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. (2002). Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2: 117–125.

    Article  CAS  PubMed  Google Scholar 

  • Tokunaga M, Ezoe S, Tanaka H, Satoh Y, Fukushima K, Matsui K et al. (2010). BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1. J Biol Chem 285: 31774–31782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Yabuki M, Harada K et al. (2004). Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol 6: 1204–1211.

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE . (2008). Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther 83: 258–264.

    Article  CAS  PubMed  Google Scholar 

  • Weisberg E, Griffin JD . (2000). Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 95: 3498–3505.

    CAS  PubMed  Google Scholar 

  • Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE et al. (2001). Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene 20: 6188–6195.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto T, Yumioka T, Sekine Y, Sato N, Minoguchi M, Yoshimura A et al. (2003). Regulation of FcepsilonRI-mediated signaling by an adaptor protein STAP-2/BSK in rat basophilic leukemia RBL-2H3 cells. Biochem Biophys Res Commun 306: 767–773.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the Grant-in-Aid for scientific research from Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Author notes

  1. Y Sekine and O Ikeda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan

    Y Sekine, O Ikeda, A Mizushima, Y Ueno, R Muromoto & T Matsuda

  2. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-Ku, Tokyo, Japan

    A Yoshimura

  3. Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Y Kanakura & K Oritani

Authors
  1. Y Sekine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Mizushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Muromoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Kanakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Oritani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Matsuda.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sekine, Y., Ikeda, O., Mizushima, A. et al. STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis. Oncogene 31, 4384–4396 (2012). https://doi.org/10.1038/onc.2011.604

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.604

Keywords

This article is cited by

Search

Advanced search

Quick links