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Molecular and Cellular Biology, November 2005, p. 9632-9645, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9632-9645.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Met/Hepatocyte Growth Factor Receptor Ubiquitination Suppresses Transformation and Is Required for Hrs Phosphorylation

Jasmine V. Abella,1,{dagger} Pascal Peschard,1,{dagger} Monica A. Naujokas,2 Tong Lin,2 Caroline Saucier,2 Sylvie Urbé,4 and Morag Park1,2,3*

Departments of Biochemistry,1 Medicine,2 Oncology, McGill University, Montréal, Québec, Canada,3 Physiological Laboratory, University of Liverpool, Liverpool, United Kingdom4

Received 13 May 2005/ Returned for modification 21 June 2005/ Accepted 9 August 2005

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.

* Corresponding author. Mailing address: Molecular Oncology Group H5.21, McGill University Health Centre, 687 Pine Ave. West, Montréal, Québec, Canada H3A 1A1. Phone: (514) 934-1934, ext. 35845. Fax: (514) 843-1478. E-mail: morag.park{at}mcgill.ca.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2005, p. 9632-9645, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9632-9645.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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