DEGRADATION OF THE MET TYROSINE KINASE RECEPTOR BY THE UBIQUITIN-PROTEASOME PATHWAY

The Met tyrosine kinase receptor is a widely expressed molecule which mediates pleiotropic cellular responses following activation by its li gand, hepatocyte growth factor/scatter factor (HGF/SF). In this commun ication we demonstrate that significant Met degradation is induced by HGF/SF and that this degradation can be blocked by lactacystin, an inh ibitor of proteasome activity. We also show that Met is rapidly polyub iquitinated in response to ligand and that polyubiquitinated Met molec ules, which are normally unstable, are stabilized by lactacystin. Both HGF/SF-induced degradation and polyubiquitination of Met were shown t o be dependent on the receptor possessing intact tyrosine kinase activ ity. Finally, we found that a normally highly labile 55-kDa fragment o f the Met receptor is stabilized by lactacystin and demonstrate that i t represents a cell-associated remnant that is generated following the ligand-independent proteolytic cleavage of the Met receptor in its ex tracellular domain. This truncated Met molecule encompasses the kinase domain of the receptor and is itself tyrosine phosphorylated. We conc lude that the ubiquitin-proteasome pathway plays a significant role in the degradation of the Met tyrosine kinase receptor as directed by li gand-dependent and -independent signals. We propose that this proteoly tic pathway may be important for averting cellular transformation by d esensitizing Met signaling following ligand stimulation and by elimina ting potentially oncogenic fragments generated via extracellular cleav age of the Met receptor.