SARA and RNF11 at the crossroads of EGFR signaling and trafficking.

The classical view that endocytosis serves only for growth factor receptor degradation and signaling termination has recently been challenged by an increasing number of reports showing that various growth factor receptors such as epidermal growth factor receptor (EGFR) continue to activate downstream signaling molecules en route to lysosomes prior to their degradation. Moreover, the trafficking route that the ligand-receptor complexes follow to enter the cell is mutually interconnected with the final signaling output. Endosomal resident effector proteins are compartmentalized and regulate the signaling and trafficking of the ligand-bound receptor complexes. Smad anchor for receptor activation (SARA) is an early endosomal protein facilitating TGF-β signaling cascade. Even though SARA was identified as an adaptor protein that regulates SMAD2 activation and TGF-β signal propagation, an increasing number of reports in various systems describe SARA as a trafficking regulator. Recently, SARA has been shown to interact with the E3 ubiquitin ligase RNF11 (RING finger protein 11) and members of the ESCRT-0 (endosomal sorting complex required for transport) complex functionally participating in the degradation of EGFR.