Fig. 7. Role of endocytosis and Lqf in sending DSL signals. (A,B) Examples of two general models are shown, distinguished by whether the activation of Notch is triggered by the early events of DSL endocytosis leading up to pinching off of the coated vesicle (A), or is dependent on the recycling of DSL ligands (B). To accommodate our results, we envisage that the first model (A) would require Lqf (red) to be present, or active, in only a subset of coated pits or other structures that provide a specialized micro-environment (dark gray) necessary for productive interactions (pink scissors) between DSL ligands and Notch. Cargo proteins, including DSL ligands (colored gold), that carry only mono-Ubiquitin internalization signals would depend on Lqf to be recruited to these specialized structures. Other adapters (blue) would internalize mono-ubiquitinated DSL ligands via other structures that lack the necessary environment for productive interactions to occur. In the second model (B), Lqf and other adapters could co-exist in coated pits, with Lqf allowing mono-ubiquitinated cargo to gain access, subsequently, to a recycling pathway. Entry into this pathway would be essential for the conversion of nascent DSL proteins into active ligands, for example by proteolytic processing (not shown), which can then interact productively with Notch. In both models, introduction of other internalization signals, such as the LDL receptor signal, would allow DSL ligands to bypass the requirement for Lqf to enter the required surface structures or recycling pathways. EE, early endosome; RE, recycling endosome; LE/MVB, late endosome/multi-vesicular body; TGN, trans-Golgi network.