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The interface of receptor trafficking and signalling

Physiological Laboratory, University of Liverpool, Crown St., Liverpool L69 3BX, UK

View larger version (69K): [in a new window]   Fig. 1. Signal transduction and the Rab5 cycle. EGF stimulation leads to opposing effects on Rab5 nucleotide status. One pathway leads to an increase in active GTP-bound Rab5 and receptor internalisation through stimulation of nucleotide exchange, possibly through PI 3-kinase activation. Conversly, EGF stimulation can also negatively regulate endocytosis by activating the GTPase activity of Rab5 through the sequential recruitment of Eps8 and RN-tre to the receptor. Stimulation of endocytosis is also observed in response to p38 MAP-kinase activation by UV or peroxide (H2O2). This effect is proposed to be mediated through phosphorylation and activation of GDI, a chaperone of cytosolic GDP-bound Rab proteins, which results in a net increase in Rab5 cycling.

View larger version (57K): [in a new window]   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).

View larger version (61K): [in a new window]   Fig. 3. Cbl, an E3 ubiquitin ligase, regulates receptor sorting and acts as an adapter protein. Schematic illustration of the differential effects on polyubiqitination and sorting of receptor tyrosine kinases (RTKs) of two Cbl mutants. (i) Ligand-induced tyrosine phosphorylation (Tyr-P) of the RTK leads to the binding of Cbl to the receptor and internalisation via clathrin-coated vesicles to the early or sorting endosome. (ii) Wild-type Cbl (c-Cbl) mediates the polyubiquitination of the receptor tail through recruitment of ubiquitin-conjugating enzymes (UBCs or E2 ligases, see insert) and concomitant sorting of the receptor to late-endosomal/lysosomal compartments where degradation takes place. The Y371F linker mutant of Cbl does not mediate polyubiquitination but can govern sorting of the receptor for degradation. The nearby Y368F linker mutation produces a Cbl mutant able to mediate polyubiquitination but incapable of re-routing the receptor from the plasma-membrane-directed recycling pathway to the lysosome. The insert shows a simplified illustration of the E3-ligase and adapter functions of Cbl. Cbl binds to the tyrosine phosphorylated (P) receptor (RTK) through its tyrosine-kinase-binding domain (TKB), which is connected to the RING-finger domain (RF) through an essential linker. The RING-finger domain recruits ubiquitin-conjugating enzymes (UBCs), which transfer ubiquitin (Ubn) onto the receptor. The RF also binds Sprouty, whereas the proline-rich domain (PPPP) binds the adapter Grb2 and Src kinase. The C-terminal domain recruits CrkL and p85-p110 PI3-kinase through phosphorylated tyrosines Y700/Y774 and Y731, respectively. For a more complete list of interactions, see Thien and Langdon, 2001 (Thien and Langdon, 2001).