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.
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.
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea.
authors.forename: K-W
authors.initials: KW
authors.lastname: Cho
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.forename: C-W
authors.initials: CW
authors.lastname: Park
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.forename: D J
authors.initials: DJ
authors.lastname: Kim
authors.forename: K J
authors.initials: KJ
authors.lastname: Kim
authors.forename: S H
authors.initials: SH
authors.lastname: Yoon
authors.forename: Y
authors.initials: Y
authors.lastname: Park
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Cho
authors.forename: S
authors.initials: S
authors.lastname: Jang
authors.forename: B-C
authors.initials: BC
authors.lastname: Park
authors.forename: S-W
authors.initials: SW
authors.lastname: Chi
authors.forename: S H
authors.initials: SH
authors.lastname: Yoo
authors.forename: M H
authors.initials: MH
authors.lastname: Jang
authors.forename: H N
authors.initials: HN
authors.lastname: Kim
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Jo
authors.forename: Y W
authors.initials: YW
authors.lastname: Park
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010455:Peptides; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met