A, Major regulatory effects of endocytosis on receptor-mediated signaling from the plasma membrane, using an RTK such as the EGF receptor (EGFR) and conventional 7TMR such as β2AR (GPCR) as examples. Regulated endocytosis via clathrin –dependent or -independent mechanisms removes receptors from accessibility to plasma membrane-associated signaling pathways, linked by a scaffold protein such as Grb2 or a heterotrimeric G protein, contributing to rapid attenuation or “desensitization” of cell signaling (violet arrows). Recycling to the plasma membrane can reverse this effect, restoring or “resensitizing” cellular responsiveness (blue arrow). Sorting of internalized receptors in MVB and fusion with lysosomes removes receptors from access to cytoplasmic effectors and promotes their proteolysis, resulting in receptor “downregulation” (orange arrows). B, Examples of several proposed regulatory loops by which activated signaling receptors regulate the endocytic pathway, as discussed and cited in the text. The EGF receptor tyrosine kinase is reported to promote coated pit formation under certain conditions (dotted blue line), inhibit early to late endosome maturation (dotted orange line) and promote involution of MVB (dotted brown line). Certain GPCRs, such as the ß2AR, reduce the rate of endocytic scission of receptor-containing coated pits (dotted violet line). C, Two recent examples of local regulation of clathrin-coated pits by activated signaling receptors. Left panel: Activated EGFRs, by a mechanism dependent on Grb2, can promote de novo clathrin coated pit formation in cells depleted of AP-2. Such AP-2-deficient coated pits concentrate activated EGFRs but not transferrin receptors (TfnRs). Right panel: GPCRs such as the ß2AR concentrate non-uniformly in clathrin-coated pits in association with the regulated adaptor β-arrestin (arrestin 2 or 3). The surface lifetime specifically of GPCR-containing coated pits is prolonged by a mechanism that requires PDZ domain mediated binding to scaffold proteins such as EBP50/NHERF1 and linkage to cortical actin via ezrin, whereas coated pits not containing concentrated GPCRs undergo endocytic scission at an unaltered rate.

The figure depicts several types of signaling thought to occur from endosomes, as discussed in the text. Distinct systems are superimposed on the minimum number of endosomal compartments consistent with the presently available data. The figure is an amalgam of data from a number of systems and cell types; thus, only a subset of the indicated signaling events would be expected to occur in any particular cell type. Ligand-induced dimerization of EGF (EGFR) Trk, TGFβ (TGFβR)and Notch is not shown to reduce complexity of the figure. I, internalization; R, recycling; D, degradation; EE, early endosomes; SE/LE, sorting/late endosomes. Endocytic and signaling pathways are shown as broken and solid lines, respectively.