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PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

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  • Frankie Chi Fat Ko

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital
    Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong)

  • Lo-Kong Chan

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital
    Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong)

  • Karen Man-Fong Sze

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital)

  • Yin-Shan Yeung

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital)

  • Edith Yuk-Ting Tse

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital)

  • Ping Lu

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital)

  • Ming-Hua Yu

    (Shanghai Pudong Hospital, 2800 Gongwei Road, Pudong)

  • Irene Oi-Lin Ng

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital
    Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong
    State Key Laboratory for Liver Research, L7-04 Laboratory Block, Faculty of Medicine Building, The University of Hong Kong)

  • Judy Wai Ping Yam

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital
    Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong
    State Key Laboratory for Liver Research, L7-04 Laboratory Block, Faculty of Medicine Building, The University of Hong Kong)

Abstract

Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that encodes a RhoGTPase-activating protein (RhoGAP) and is frequently inactivated in many human cancers. The RhoGAP activity of DLC1 against Rho signalling is well documented and is strongly associated with the tumour suppressor functions of DLC1. However, the mechanism by which the RhoGAP activity of DLC1 is regulated remains obscure. Here, we report that phosphorylation of DLC1 at Ser549 by cyclic AMP-dependent protein kinase A contributes to enhanced RhoGAP activity and promotes the activation of DLC1, which suppresses hepatoma cell growth, motility and metastasis in both in vitro and in vivo models. Intriguingly, we found that Ser549 phosphorylation induces the dimerization of DLC1 and that inducible dimerization of DLC1 can rescue the tumour suppressive and RhoGAP activities of DLC1 containing a Ser549 deletion. Our study establishes a novel regulatory mechanism for DLC1 RhoGAP activity via dimerization induced by protein kinase A signalling.

Suggested Citation

  • Frankie Chi Fat Ko & Lo-Kong Chan & Karen Man-Fong Sze & Yin-Shan Yeung & Edith Yuk-Ting Tse & Ping Lu & Ming-Hua Yu & Irene Oi-Lin Ng & Judy Wai Ping Yam, 2013. "PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis," Nature Communications, Nature, vol. 4(1), pages 1-14, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2604
    DOI: 10.1038/ncomms2604
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