Figure 3. Cellular model of how actin based asymmetry in endocytosis may determine polarized downstream signaling. (A) The “fence and picket” model³⁶ predicts that the actin cortex partitions the plasma membrane into domains with potentially variable molecular properties. As a consequence, differences in the actin cytoskeleton may be present at the dorsal and ventral side of the cell due to the presence or absence of spatial cues (as adhesion surfaces). The actin network defines uptake mechanisms that will be preferentially employed at distinct sites. Different ligands (at different concentrations) show a preference for different uptake mechanisms and thus will be endocytosed asymmetrically. Ligand internalization initiates signaling cascades that will only be sustained when downstream effectors are locally higher concentrated than the total average cell concentration (are polarized). As a consequence, polarized endocytosis of ligands concentrates distribution of downstream signaling gradients, thus propagating signals from the extracellular into the intracellular space and allowing cells to sense their environment. (B) Upon disruption of the actin cytoskeleton effectors downstream of membrane receptors are recruited to the entire surface of the plasma membrane. This recruitment to a larger surface leads to a decrease in the local concentration of downstream effectors, not allowing signal propagation.