Panel A shows schematic models of CD36WT and CD36G12V organization across peripheral and central membrane regions with tetraspanin, integrin, caveolae, and actin. Panel B shows schematic models of CD36WT and CD36G12V signaling before and after TSP-1 stimulation, illustrating Fyn, signaling events, and actin organization across peripheral and central membrane regions.
Schematic models of CD36 localization, interactions, and coupling to CA, as well as signaling via the SFK Fyn. (A) Illustration of the multi-faceted organization of CD36 at the PM of MVECs. In the WT case, CD36 is more abundant in the periphery region (<4 μm from the cell edge) than in the center region (>4 μm from the cell edge). In the periphery, CD36 associates with multimolecular assemblies containing integrins and tetraspanins, which in turn help link it to CA. In the center region, CD36 associates less with integrins and tetraspanins, and instead localizes more in caveolae. Disruption of CD36’s interactions with integrins and tetraspanins via the G12V point mutation (which weakens interactions and eliminates detectable CD36 association with integrin/tetraspanin multimolecular assemblies) weakens the link between CD36 and CA and shifts CD36 localization from the periphery to the center, leading to increased CD36 localization in caveolae. CD36 mobility also changes, where it exhibits more—but weaker—confinement, due to factors beyond CA (not shown in schematic). Arrows indicate that CD36 associated with integrins and tetraspanins can link to CA. Asterisks denote CD36 localized in caveolae (with probably altered link to CA). Solid/dashed ovals indicate the stronger/weaker three-way assemblies in the periphery/center. (B) Illustration of CD36-Fyn interactions and signaling in response to TSP-1. In the basal state, CD36WT is significantly localized with Fyn, particularly in the periphery region, where there is weak tonic Fyn signaling. TSP-1 stimulation leads to stronger Fyn activation and signaling, but still only in the periphery. On the other hand, CD36G12V displays elevated localization with Fyn in the center region, associated with strong Fyn signaling in the basal state. Furthermore, TSP-1 stimulation decreases Fyn activation rather than increasing it, abolishing it in the center and weakening it in the periphery. These results suggest that disruption of CD36’s interaction landscape and organization (including CD36-actin coupling) leads to aberrant, ligand-insensitive signaling and impaired regulatory control.