Identification of a pivotal endocytosis motif in c-Met and selective modulation of HGF-dependent aggressiveness of cancer using the 16-mer endocytic peptide = c-Met의 핵심 엔도싸이토시스 모티프의 발견과 16-mer 펩타이드를 이용한 HGF-의존적 암의 선택적 조절

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Title
Identification of a pivotal endocytosis motif in c-Met and selective modulation of HGF-dependent aggressiveness of cancer using the 16-mer endocytic peptide = c-Met의 핵심 엔도싸이토시스 모티프의 발견과 16-mer 펩타이드를 이용한 HGF-의존적 암의 선택적 조절
Author(s)
Kyu-Won 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; Byoung Chul ParkSeung-Wook Chi; S H Yoo; M H Jang; H N Kim; E Kim; K Jo; Young Woo Park
Bibliographic Citation
Oncogene, vol. 32, no. 8, pp. 1018-1029
Publication Year
2013
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.
ISSN
0950-9232
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/onc.2012.122
Type
Article
Appears in Collections:
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
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