Fig. 2. Hrs is an adapter molecule implicated in endosomal sorting. Proposed mechanism by which Hrs mediates downregulation of EGFR by recruiting sorting nexin 1 (SNX). (i) EGF binding induces tyrosine phosphorylation of EGFR, causing its internalisation by clathrin-coated vesicles (CCV) to an early or sorting endosome. Hrs is recruited to the early endosome through PtdIns(3)P-binding to its FYVE domain and associates with endosomal sorting nexin. (ii) The coincident translocation of the EGFR from the plasma membrane and Hrs from the cytosol to the endosome results in the tyrosine phosphorylation of Hrs. This in turn leads to the dissociation of the tyrosine-phosphorylated Hrs from the membrane and we speculate may liberate the sorting nexin to bind the EGFR and route it to the late endosome and lysosome for degradation. The insert shows a simplified illustration of the adapter function of Hrs. Hrs binding to the membrane is partially dependent on PtdIns(3)P interaction with its FYVE domain. Hrs is linked to the EGFR by interaction of a proline-rich domain with Eps15, which also binds to EAST, a STAM/Hbp homologue. SNX1 binds to a region encompassing the proline-rich domain and the coiled-coil domain of Hrs. The major coiled-coil domain of Hrs interacts with STAM and Hbp, as well as with SNAP25. Hrs also interacts with the NF2 gene product, Schwannomin (also known as Merlin). STAM/Hbp in turn recruits the protein AMSH and the de-ubiquitination enzyme UBPY through an SH3 domain. For detailed domain structures see Komada and Kitamura, 2001 (Komada and Kitamura, 2001).