Down-regulation of MET, the receptor for hepatocyte growth factor

The ligand-dependent degradation of activated tyrosine kinase receptors pro vides a means by which mitogenic signalling can be attenuated. In many cell types the ligand-dependent degradation of the tyrosine kinase receptor Met is completely dependent on the activity of the 26S proteasome (Jeffers et al,, 1997b), We now show that degradation also requires trafficking to late endosomal compartments and the activity of acid dependent proteases as det ermined by the effects of a dominant negative form of dynamin (K44A) and a vacuolar-ATPase inhibitor, concanamycin, We show that in the presence of th e proteasome inhibitor lactacystin, Met fails to redistribute from the plas ma membrane to intracellular compartments. This observation is most consist ent with the interpretation that proteasome activity is required for Met in ternalization and only indirectly for its degradation.