title: Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification.
abstract: BACKGROUND
  MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification.
  
  
  METHODS
  With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays.
  
  
  RESULTS
  We identified epidermal growth factor receptor (EGFR), human EGFR (HER)2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling.
  
  
  CONCLUSIONS
  Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Tanizaki
authors.forename: I
authors.initials: I
authors.lastname: Okamoto
authors.forename: K
authors.initials: K
authors.lastname: Sakai
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019281:Dimerization; D066246:ErbB Receptors / Q000378:metabolism*; D005784:Gene Amplification; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051096:Proto-Oncogene Proteins c-ret; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D017978:Receptors, Growth Factor; C491743:MET protein, human