Control of growth factor receptor dynamics by reversible ubiquitination

Activated tyrosine kinase receptors acquire ubiquitin tags. Ubiquitination governs receptor down-regulation through interaction with components of the endosomal ESCRT (endosomal sorting complexes required for transport) machinery that shepherds receptors into luminal vesicles of multivesicular bodies en route to the lysosome. We have characterized two de-ubiquitinating enzymes that interact with components of this machinery. AMSH [associated molecule with the SH3 domain (Src homology 3 domain) of STAM (signal transducing adapter molecule)] shows specificity for Lys⁶³- over Lys⁴⁸-linked ubiquitin and may act to rescue receptors from taking the lysosomal pathway. In contrast, UBPY (ubiquitin-specific processing protease Y) does not discriminate between Lys⁴⁸ and Lys⁶³-linked chains and is required for lysosomal sorting.