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.
Highlights
Cbl Protein Levels Are Elevated following Inhibition of Met Kinase—To establish whether amplification of MET in the Okajima, MKN45, Snu-5, and KATO II gastric cancer cell lines leads to constitutive activation of Met protein [10], proteins from whole cell lysates were immunoblotted with Met and phospho-Met antibodies (Fig. 1, A and B)
Considering that c-Cbl protein levels are increased upon inhibition of the proteasome, we assessed whether c-Cbl is ubiquitinated under basal conditions in gastric cancer cells
Members of the Cbl family can serve as negative regulators for many tyrosine kinases, and loss of Cbl-dependent negative regulation is recognized as a mechanism that contributes to tumorigenesis [43]
Summary
We show that Met-dependent loss of Cbl protein in MET-amplified gastric cancer cell lines represents another mechanism contributing to signal dysregulation. Spliced mutants of Met that result in the excision of exon 14 containing the Cbl TKB domain binding site (Tyr-1003) have been identified in both non-small cell lung cancer cell lines and adenocarcinoma lung tumors [32,33,34] These Met variants show enhanced stability and prolonged signaling and oncogenic capacity [33]. We show that conditions in which MET is amplified in human gastric cancers leads to the loss of Cbl protein This reflects another mechanism through which Met is able to uncouple from Cbl-dependent negative regulation. This represents a mechanism of RTK cross-talk in human tumors whereby Cbl loss is dependent on Met kinase activity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
