Fig. 8.

Proposed model for p75^NTR signaling on the plasma membrane. (A) Model of the membrane partitioning undergone by wt p75^NTR (Left, green) or mut p75^NTR (Right, green) upon NGF (orange) binding. Cholesterol-rich, signaling-competent regions are represented with increased membrane thickness and containing cholesterol and gangliosides. Partitioning is highlighted by the arrows in opposite directions. (B) Model of p75^NTR signaling at the membrane and downstream internalization. Signaling can occur from cholesterol-poor or cholesterol-rich membrane regions, resulting in receptor internalization within clathrin-positive (green) or caveolin-positive (red) endosomes. In our model, interactors of surface-retained p75^NTR (magenta), involved in actin remodeling and growth cone collapse, are more abundant in nonraft regions as this pathway is not impaired by the mutations introduced in mut p75^NTR. Conversely, apoptotic signaling effectors (light and dark blue) are enriched in raft platforms being efficiently activated only by NGF-bound wt p75^NTR. Different from mature NTs, proNTs at the growth cones cause surface accumulation of p75^NTR, which could arise from internalization inhibition (as for Dynasore and Pitstop2 treatments or expression of the dominant negative K44A dynamin) or by increased receptor recycling at the membrane.