title: The C-terminus of Hsp70-interacting protein promotes Met receptor degradation.
abstract: BACKGROUND
  The tyrosine kinase Met receptor regulates a complex array of cellular behaviors known collectively as invasive growth. Although essential for normal development and wound repair, this pathway is frequently deregulated in tumors to promote their growth, motility, and invasion. Accordingly, Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with a poor patient prognosis. Previous studies have shown that Met receptor levels are governed in part by Cbl-mediated ubiquitination and degradation, and the uncoupling of Met from this pathway promotes its transforming activity.
  
  
  METHODS
  Here, we describe a novel mechanism of Met degradation in Non Small Cell Lung Cancer Cells and HeLa cells using western blot, immunocytochemistry, immunoprecipitation assay, invasion assay, cell viability assay and in vivo tumor growth model.
  
  
  RESULTS
  Met receptor interacted with the C-terminus of heat shock protein 70-interacting protein (CHIP), leading to proteasomal degradation of the receptor in vitro. In addition, CHIP overexpression destabilized endogenous Met receptor in lung cancer cells, whereas CHIP knockdown increased Met receptor expression, indicating an essential role for CHIP in the regulation of Met degradation. CHIP overexpression inhibited Met-mediated lung cancer cell growth and invasion. Finally, we confirmed these results by tumor xenograft model.
  
  
  CONCLUSIONS
  Based on these findings, we conclude that CHIP is a suppressor of Met function, serving to regulate cellular receptor levels by promoting Met receptor degradation.
authors.affiliation: Infection Signaling Network Research Center, Chungnam National University, Daejeon, South Korea.
authors.forename: Kang Won
authors.initials: KW
authors.lastname: Jang
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Min-Woong
authors.initials: MW
authors.lastname: Kang
authors.forename: Myung Hoon
authors.initials: MH
authors.lastname: Na
authors.forename: Choong Sik
authors.initials: CS
authors.lastname: Lee
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Song
authors.forename: Seung Pyung
authors.initials: SP
authors.lastname: Lim
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D012333:RNA, Messenger; D017978:Receptors, Growth Factor; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met