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Smurf1 regulates lung cancer cell growth and migration through interaction with and ubiquitination of PIPKIγ

Oncogene volume 36, pages 5668–5680 (2017)Cite this article

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Abstract

Type Iγ phosphatidylinositol phosphate kinase (PIPKIγ), a phospholipid kinase generating PIP2, is positively expressed in breast cancer tissues, which correlates intimately with the progression of patients. However, little is known about the expression level of PIPKIγ in patients with other cancer types as well as their underlying regulation mechanisms. Here, we report that PIPKIγ is highly expressed in lung cancer tissues and its expression level is critical for lung cancer cell proliferation, which may serve as a prognostic marker for lung cancer patients. Meanwhile, we show that E3 ubiquitin ligase Smurf1 directly interacts with PIPKIγ and targets PIPKIγ for ubiquitination and degradation in lung cancer cells. Also, we discover that Smurf1 directly binds to the kinase domain of PIPKIγ via its C2 domain while Lysine 255 in PIPKIγ acts as the major ubiquitin acceptor site for Smurf1. In addition, we demonstrate that the phosphorylation mimicking mutant of Smurf1, Smurf1 T306D, prevents PIPKIγi2 from ubiquitination and subsequent degradation similar to the effect of forskolin-potentiated cAMP formation, suggesting that Thr306 in Smurf1 is critical for its phosphorylation by PKA. Moreover, PKA-Smurf1-PIPKIγ signal transduction takes a significant part in lung cancer cell growth and in vivo tumorigenesis. Thus, we propose that the PKA-Smurf1-PIPKIγ pathway has an important role in pulmonary tumorigenesis and imposes substantial clinical impact on development of novel diagnostic markers and therapeutic targets for lung cancer treatment.

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Acknowledgements

We thank Dr Dianqing Wu, Jian Luo, Hongrui, Wang, and Lingqiang Zhang for kindly providing reagents. We also appreciate the assistance from other members of the lab. This work was supported by grants from National Basic Research Program of China (973 program 2012CB910404 and 2010CB529704), National Natural Science Foundation of China (30971521, 81502559, 81500112, 81602515, 81572645, 30800587 and 31171338), grant from the Science and Technology Commission of Shanghai Municipality (11DZ2260300) and the Science and Technology Commission of Pudong New Area Foundation (PKJ2016-Y37).

Author contributions

HL, YW, NX and XG designed the research; HL, YW and RW performed research; HL, YW, RW and XG analyzed the data; HL, NX and XG wrote the paper.

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  1. H Li, N Xiao, Y Wang and R Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China

    H Li & X Ge

  2. Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    H Li

  3. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China

    H Li, N Xiao, Y Wang, Y Chen, W Pan, D Liu, S Li, J Sun & K Zhang

  4. Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Institute of Traumatic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    N Xiao

  5. Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China

    Y Wang

  6. Department of Thoracic Surgery, Cancer Hospital, Cancer Institute of Fudan University, Shanghai, China

    R Wang

  7. Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    Y Sun

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Li, H., Xiao, N., Wang, Y. et al. Smurf1 regulates lung cancer cell growth and migration through interaction with and ubiquitination of PIPKIγ. Oncogene 36, 5668–5680 (2017). https://doi.org/10.1038/onc.2017.166

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