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Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis

Author

Listed:
  • Tao Han

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Shulong Jiang

    (H. Lee Moffitt Cancer Center and Research Institute
    Affiliated Jining NO.1 People’s Hospital of Jining Medical University
    Guang’anmen Hospital, China Academy of Chinese Medical Sciences)

  • Hong Zheng

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Qing Yin

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Mengyu Xie

    (H. Lee Moffitt Cancer Center and Research Institute
    University of South Florida)

  • Margaret R Little

    (H. Lee Moffitt Cancer Center and Research Institute
    Nova Southeastern University)

  • Xiu Yin

    (H. Lee Moffitt Cancer Center and Research Institute
    Affiliated Jining NO.1 People’s Hospital of Jining Medical University)

  • Ming Chen

    (Beth Israel Deaconess Medical Center, Harvard Medical School
    Duke University School of Medicine, Duke Cancer Institute, Duke University)

  • Su Jung Song

    (Beth Israel Deaconess Medical Center, Harvard Medical School
    Soonchunhyang University)

  • Amer A. Beg

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Pier Paolo Pandolfi

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Lixin Wan

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

Abstract

The Anaphase Promoting Complex (APC) coactivator Cdh1 drives proper cell cycle progression and is implicated in the suppression of tumorigenesis. However, it remains elusive how Cdh1 restrains cancer progression and how tumor cells escape the inhibition of Cdh1. Here we report that Cdh1 suppresses the kinase activity of c-Src in an APC-independent manner. Depleting Cdh1 accelerates breast cancer cell proliferation and cooperates with PTEN loss to promote breast tumor progression in mice. Hyperactive c-Src, on the other hand, reciprocally inhibits the ubiquitin E3 ligase activity of APCCdh1 through direct phosphorylation of Cdh1 at its N-terminus, which disrupts the interaction between Cdh1 and the APC core complex. Furthermore, pharmacological inhibition of c-Src restores APCCdh1 tumor suppressor function to repress a panel of APCCdh1 oncogenic substrates. Our findings reveal a reciprocal feedback circuit of Cdh1 and c-Src in the crosstalk between the cell cycle machinery and the c-Src signaling pathway.

Suggested Citation

  • Tao Han & Shulong Jiang & Hong Zheng & Qing Yin & Mengyu Xie & Margaret R Little & Xiu Yin & Ming Chen & Su Jung Song & Amer A. Beg & Pier Paolo Pandolfi & Lixin Wan, 2019. "Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11618-7
    DOI: 10.1038/s41467-019-11618-7
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