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- W2100991907 abstract "The Met receptor tyrosine kinase (RTK) regulates epithelial remodeling, dispersal, and invasion and is deregulated in many human cancers. It is now accepted that impaired down-regulation, as well as sustained activation, of RTKs could contribute to their deregulation. Down-regulation of the Met receptor involves ligand-induced internalization, ubiquitination by Cbl ubiquitin ligases, and lysosomal degradation. Here we report that a ubiquitination-deficient Met receptor mutant (Y1003F) is tumorigenic in vivo. The Met Y1003F mutant is internalized, and undergoes endosomal trafficking with kinetics similar to the wild-type Met receptor, yet is inefficiently targeted for degradation. This results in sustained activation of Met Y1003F and downstream signals involving the Ras-mitogen-activated protein kinase pathway, cell transformation, and tumorigenesis. Although Met Y1003F undergoes endosomal trafficking and localizes with the cargo-sorting protein Hrs, it is unable to induce phosphorylation of Hrs. Fusion of monoubiquitin to Met Y1003F is sufficient to decrease Met receptor stability and prevent sustained MEK1/2 activation. In addition, this rescues Hrs tyrosine phosphorylation and decreases transformation in a focus-forming assay. These results demonstrate that Cbl-dependent ubiquitination is dispensable for Met internalization but is critical to target the Met receptor to components of the lysosomal sorting machinery and to suppress its inherent transforming activity." @default.
- W2100991907 created "2016-06-24" @default.
- W2100991907 creator A5011593105 @default.
- W2100991907 creator A5019964520 @default.
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- W2100991907 creator A5046025321 @default.
- W2100991907 creator A5080038642 @default.
- W2100991907 creator A5088293962 @default.
- W2100991907 date "2005-11-01" @default.
- W2100991907 modified "2023-10-16" @default.
- W2100991907 title "Met/Hepatocyte Growth Factor Receptor Ubiquitination Suppresses Transformation and Is Required for Hrs Phosphorylation" @default.
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- W2100991907 doi "https://doi.org/10.1128/mcb.25.21.9632-9645.2005" @default.
- W2100991907 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1265818" @default.
- W2100991907 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16227611" @default.
- W2100991907 hasPublicationYear "2005" @default.
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