Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.

Leiser, Dominic; Pochon, Benoît; Blank Wieslawa, Elzbieta; Francica, Paola; Glück, Astrid; Aebersold, Daniel; Zimmer, Yitzhak; Medova, Michaela (2014). Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation. FEBS letters, 588(5), pp. 653-658. Elsevier 10.1016/j.febslet.2013.12.025

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The MET receptor tyrosine kinase is deregulated primarily via overexpression or point mutations in various human cancers and different strategies for MET inhibition are currently evaluated in clinical trials. We observed by Western blot analysis and by Flow cytometry that MET inhibition by different MET small molecule inhibitors surprisingly increases in a dose-dependent manner total MET levels in treated cells. Mechanistically, this inhibition-related MET accumulation was associated with reduced Tyr1003 phosphorylation and MET physical association with the CBL ubiquitin ligase with concomitant decrease in MET ubiquitination. These data may suggest careful consideration for design of anti-MET clinical protocols.

Item Type:

 Journal Article (Original Article)

Division/Institute:

 04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

UniBE Contributor:

 Leiser, Dominic, Pochon, Benoît, Blank Wieslawa, Elzbieta, Francica, Paola, Glück, Astrid Andreina, Aebersold, Daniel Matthias, Zimmer, Yitzhak, Medova, Michaela

Subjects:

 600 Technology > 610 Medicine & health

ISSN:

 0014-5793

Publisher:

 Elsevier

Language:

 English

Submitter:

 Beatrice Scheidegger

Date Deposited:

 11 Mar 2015 15:41

Last Modified:

 02 Mar 2023 23:25

Publisher DOI:

 10.1016/j.febslet.2013.12.025

PubMed ID:

 24440350

Uncontrolled Keywords:

 CBL, MET, MET Tyr1003, Receptor downregulation, Receptor ubiquitination, Small molecule tyrosine kinase inhibitor

BORIS DOI:

 10.7892/boris.61622

URI:

 https://boris.unibe.ch/id/eprint/61622

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