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CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

Oncogene volume 31, pages 5123–5131 (2012)Cite this article

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Abstract

Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-β (TGF-β) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-β target genes, PAI-I and CDK inhibitors such as p15INK4b and p21Cip1. Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-β transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-β tumor suppressor activity.

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Acknowledgements

This work was supported by a National Research Foundation grant of Korea (2009-0081756 and 2011-0014281) funded by the Korea government. We thank H Kim, W Joo, Y Kim and J Park for their technical supporting.

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Authors and Affiliations

  1. Department of Biomedical Science, CHA University, Seoul, Korea

    J M Kang, S Park, S J Kim & S-J Kim

  2. Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea

    H Y Hong & S-J Kim

  3. Department of Surgery, Gangnam Severance Hospital, Yonsei University Medical College, Seoul, Korea

    J Jeong

  4. Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, USA

    H-S Kim & S-J Kim

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  1. J M Kang
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  2. S Park
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Correspondence to S-J Kim.

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Kang, J., Park, S., Kim, S. et al. CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling. Oncogene 31, 5123–5131 (2012). https://doi.org/10.1038/onc.2012.18

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