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Identification of a pivotal endocytosis motif in c-Met and selective modulation of HGF-dependent aggressiveness of cancer using the 16-mer endocytic peptide

Oncogene volume 32, pages 1018–1029 (2013)Cite this article

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Abstract

Since c-Met has an important role in the development of cancer, it is considered as an attractive target for cancer therapy. Although molecular mechanisms for oncogenic property of c-Met have been actively investigated, regulatory elements for c-Met endocytosis and its effect on c-Met signaling remain unclear. In this study, we identified a pivotal endocytic motif in c-Met and tested it for selective modulation of HGF-induced c-Met response. Using various chimeric constructs with the cytoplasmic tail of c-Met, we were able to demonstrate that a dileucine motif located in the C-terminus of c-Met acts to regulate its endocytosis. Synthetic peptide Ant-3S, consisting of antennapedia-derived protein transduction domain (designated as Ant) and c-Met-derived 16 amino-acids (designated as 3S, spanning amino-acids 1378 to 1393), rapidly moved into cancer cells and disrupted c-Met trafficking. Importantly, an extension of c-Met retention time on the membrane by Ant-3S peptide significantly decreased phosphorylation-dependent c-Met signal transduction. Additionally, the peptide effectively inhibited HGF-induced cell growth, scattering and migration. The underlying molecular mechanism for these observations has been investigated and revealed that the dileucine motif interacts with endocytic machinery, including adaptin β and caveolin-1, for sustained and enhanced signal transduction. Finally, Ant-3S peptide specifically blocked internalization of interleukin-2 receptor α-subunit/3S chimeric protein, but not the other receptors, including Glut4, Glut8 and transferrin receptor. Such results indicate the presence of a selective endocytic assembly for c-Met. It also suggests a potential for c-Met-specific anti-cancer therapy using the identified endocytic motif in this study.

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Acknowledgements

We thank the members of the Kiwon and Young Woo laboratory for their inputs and discussions. We thank Julie Kim and Oh Gordon Chong for editing. This work was supported by the Ministry of Knowledge Economy (Regional R&D Cluster Project B0009735) of Korea.

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  1. K-W Cho and J H Park: These authors contributed equally to this work.

Authors and Affiliations

  1. Aging Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea

    K-W Cho, J H Park, C-W Park, D Lee, E Lee, D J Kim, K J Kim, S H Yoon, Y Park, E Kim, S Cho, S Jang, B-C Park & Y W Park

  2. College of Biological Sciences and Biotechnology, Chungnam National University, Daejeon, Korea

    J H Park & E Kim

  3. Medical Proteomics Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea

    S-W Chi

  4. A&R Therapeutics, Daejeon, Korea

    S H Yoo, M H Jang & H N Kim

  5. National OncoVenture, National Cancer Center, Goyang, Korea

    K Jo

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Cho, KW., Park, J., Park, CW. et al. Identification of a pivotal endocytosis motif in c-Met and selective modulation of HGF-dependent aggressiveness of cancer using the 16-mer endocytic peptide. Oncogene 32, 1018–1029 (2013). https://doi.org/10.1038/onc.2012.122

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