title: Met kinase-dependent loss of the E3 ligase Cbl in gastric cancer.
abstract: Strict regulation of signaling by receptor tyrosine kinases (RTKs) is essential for normal biological processes, and disruption of this regulation can lead to tumor initiation and progression. Signal duration by the Met RTK is mediated in part by the E3 ligase Cbl. Cbl is recruited to Met upon kinase activation and promotes ubiquitination, trafficking, and degradation of the receptor. The Met RTK has been demonstrated to play a role in various types of cancer. Here, we show that Met-dependent loss of Cbl protein in MET-amplified gastric cancer cell lines represents another mechanism contributing to signal dysregulation. Loss of Cbl protein is dependent on Met kinase activity and is partially rescued with a proteasome inhibitor, lactacystin. Moreover, Cbl loss not only uncouples Met from Cbl-mediated negative regulation but also releases other Cbl targets, such as the EGF receptor, from Cbl-mediated signal attenuation. Thus, Met-dependent Cbl loss may also promote cross-talk through indirect enhancement of EGF receptor signaling.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: Lai
authors.forename: Michael
authors.initials: M
authors.lastname: Durrant
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zuo
authors.forename: Colin D H
authors.initials: CD
authors.lastname: Ratcliffe
authors.forename: Morag
authors.initials: M
authors.lastname: Park
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
chemical_list: D061988:Proteasome Inhibitors; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D046988:Proteasome Endopeptidase Complex; C067419:CBL protein, human